Solar-powered O2 delivery for the treatment of children with hypoxaemia in Uganda: a stepped-wedge, cluster randomised controlled trial.

BACKGROUND: Supplemental O2 is not always available at health facilities in low-income and middle-income countries (LMICs). Solar-powered O2 delivery can overcome gaps in O2 access, generating O2 independent of grid electricity. We hypothesized that installation of solar-powered O2 systems on the paediatrics ward of rural Ugandan hospitals would lead to a reduction in mortality among hypoxaemic children. METHODS: In this pragmatic, country-wide, stepped-wedge, cluster randomised controlled trial, solar-powered O2 systems (ie, photovoltaic cells, battery bank, and O2 concentrator) were sequentially installed at 20 rural health facilities in Uganda. Sites were selected for inclusion based on the following criteria: District Hospital or Health Centre IV with paediatric inpatient services; supplemental O2 on the paediatric ward was not available or was unreliable; and adequate space to install solar panels, a battery bank, and electrical wiring. Allocation concealment was achieved for sites up to 2 weeks before installation, but the study was not masked overall. Children younger than 5 years admitted to hospital with hypoxaemia and respiratory signs were included. The primary outcome was mortality within 48 h of detection of hypoxaemia. The statistical analysis used a linear mixed effects logistic regression model accounting for cluster as random effect and calendar time as fixed effect. The trial is registered at ClinicalTrials.gov, NCT03851783. FINDINGS: Between June 28, 2019, and Nov 30, 2021, 2409 children were enrolled across 20 hospitals and, after exclusions, 2405 children were analysed. 964 children were enrolled before site randomisation and 1441 children were enrolled after site randomisation (intention to treat). There were 104 deaths, 91 of which occurred within 48 h of detection of hypoxaemia. The 48 h mortality was 49 (5·1%) of 964 children before randomisation and 42 (2·9%) of 1440 (one individual did not have vital status documented at 48 h) after randomisation (adjusted odds ratio 0·50, 95% CI 0·27-0·91, p=0·023). Results were sensitive to alternative parameterisations of the secular trend. There was a relative risk reduction of 48·7% (95% CI 8·5-71·5), and a number needed to treat with solar-powered O2 of 45 (95% CI 28-230) to save one life. Use of O2 increased from 484 (50·2%) of 964 children before randomisation to 1424 (98·8%) of 1441 children after randomisation (p<0·0001). Adverse events were similar before and after randomisation and were not considered to be related to the intervention. The estimated cost-effectiveness was US$25 (6-505) per disability-adjusted life-year saved. INTERPRETATION: This stepped-wedge, cluster randomised controlled trial shows the mortality benefit of improving O2 access with solar-powered O2. This study could serve as a model for scale-up of solar-powered O2 as one solution to O2 insecurity in LMICs. FUNDING: Grand Challenges Canada and The Women and Children's Health Research Institute.

Rhabdomyolysis, Acute Kidney Injury, and Mortality in Ebola Virus Disease: Retrospective Analysis of Cases From the Eastern Democratic Republic of the Congo, 2019.

BACKGROUND: Skeletal muscle injury in Ebola virus disease (EVD) has been reported, but its association with morbidity and mortality remains poorly defined. METHODS: This retrospective study included patients admitted to 2 EVD treatment units over an 8-month period in 2019 during an EVD epidemic in the Democratic Republic of the Congo. RESULTS: An overall 333 patients (median age, 30 years; 58% female) had at least 1 creatine kinase (CK) measurement (n = 2229; median, 5/patient [IQR, 1-11]). Among patients, 271 (81%) had an elevated CK level (>380 U/L); 202 (61%) had rhabdomyolysis (CK >1000 IU/L); and 45 (14%) had severe rhabdomyolysis (≥5000 U/L). Among survivors, the maximum CK level was a median 1600 (IQR, 550-3400), peaking 3.4 days after admission (IQR, 2.3-5.5) and decreasing thereafter. Among fatal cases, the CK rose monotonically until death, with a median maximum CK level of 2900 U/L (IQR, 1500-4900). Rhabdomyolysis at admission was an independent predictor of acute kidney injury (adjusted odds ratio, 2.2 [95% CI, 1.2-3.8]; P = .0065) and mortality (adjusted hazard ratio, 1.7 [95% CI, 1.03-2.9]; P = .037). CONCLUSIONS: Rhabdomyolysis is associated with acute kidney injury and mortality in patients with EVD. These findings may inform clinical practice by identifying laboratory monitoring priorities and highlighting the importance of fluid management.

Soluble Urokinase-Type Plasminogen Activator Receptor as a Prognostic Marker of Ugandan Children at Risk of Severe and Fatal Malaria.

BACKGROUND: Current malaria diagnostic tests do not reliably identify children at risk of severe and fatal infection. Host immune and endothelial activation contribute to malaria pathogenesis. Soluble urokinase-type plasminogen activator receptor (suPAR) is a marker of these pathways. We hypothesized that measuring suPAR at presentation could risk-stratify children with malaria. METHODS: Plasma suPAR levels were determined in consecutive febrile children with malaria at presentation to hospital in Jinja, Uganda. We evaluated the accuracy of suPAR in predicting in-hospital mortality, and whether suPAR could improve a validated clinical scoring system (Lambaréné Organ Dysfunction Score [LODS]). RESULTS: Of the 1226 children with malaria, 39 (3.2%) died. suPAR concentrations at presentation were significantly higher in children who went on to die than in those who survived (P < .0001). suPAR levels were associated with disease severity (LODS: 0 vs 1, P = .001; 1 vs 2, P < .001; 2 vs 3, 0 vs 2, 1 vs 3, and 0 vs 3, P < .0001). suPAR concentrations were excellent predictors of in-hospital mortality (area under the receiver operating characteristic curve [AUROC], 0.92 [95% confidence interval {CI}, .91-.94]). The prognostic accuracy of LODS (AUROC, 0.93 [95% CI, .91-.94]) was improved when suPAR was added (AUROC, 0.97 [95% CI, .96-.98]; P < .0001). CONCLUSIONS: Measuring suPAR at presentation can identify children at risk of severe and fatal malaria. Adding suPAR to clinical scores could improve the recognition and triage of children at risk of death. suPAR can be detected with a point-of-care test and can now be evaluated in prospective trials.

Evolution of prevention of vertical HIV transmission in Uganda: 2008-2017.

OBJECTIVES: Uganda adapted its policy for prevention of vertical transmission (VT) of HIV transmission as the World Health Organization released Options A, B and B+. We assessed trends in diagnostic testing, breastfeeding practices, maternal and infant antiretroviral therapy (ART), mortality, VT and HIV-free survival (HFS) among Ugandan infants born to women living with HIV during this period of successive guideline changes. METHODS: This is is a retrospective observational study of infants attending early infant diagnosis clinics at two Ugandan hospitals. RESULTS: A total of 1885 infants (48% female) were managed from 2009 to 2017. DNA polymerase chain reaction (PCR) for early infant diagnosis was performed on 1719 infants (92%, one or more PCR tests) and 676 infants (36%, two PCR tests). HIV serology was performed on 90 infants (4.8%). Testing increased over the study period but remained suboptimal, due to high loss to follow-up (LTFU). A total of 93% of infants were breastfed, for a median of 9.5 months. The duration of breast milk exposure increased over the study period, consistent with guidelines that increasingly encouraged breastfeeding. Nine cases (0.48%) of suspected breast milk transmission were observed. The use of ART increased significantly over the study period. Mortality (3.5%, 2.7% and 1.1%; p = 0.0076) and VT (17%, 12% and 7.4%; p < 0.0001) decreased over the study period (2008-2010, 2011-2012 and 2013-2017, respectively). LTFU values were 31%, 49% and 59% at 6, 12 and 18 months of age, respectively, with only modest improvements over time. HFS could only be conclusively documented in 532 infants (28%) because of LTFU. CONCLUSIONS: From 2009 to 2017, outcomes improved among HIV-exposed infants in Uganda. LTFU remains a barrier to optimal care.

Access to healthcare services and confidence in healthcare professionals' management of malaria: the views of Francophone sub-Saharan African Immigrants living in western Canada.

BACKGROUND: There is a paucity of knowledge about the healthcare attitudes and practices of French-speaking immigrants originating from Sub-Saharan Africa (FISSA) living in minority settings. The purpose of this study was to characterize FISSA healthcare experiences and confidence in the malaria-related knowledge of health professionals in Edmonton. METHODS: A structured survey was used to examine a cohort of 382 FISSA (48% female; 52% male) living in Edmonton. FISSA general healthcare attitudes, experiences and satisfaction with the Canadian healthcare system were studied. Healthcare Competency Perception (HCP) was characterized by using an index score. Statistical analyses were performed to evaluate the impact of healthcare experiences and other outcomes. RESULTS: Intriguingly, while only 42% of FISSA had a French-speaking family physician, 83% (197/238) of those who had received health care services in Alberta found that access to medical treatment was easy, and 77% (188/243) were satisfied with received care. Although 70% (171/243) of FISSA did not receive services in French, 82% (199/243) surprisingly reported having good levels of comprehension during their visits. Satisfaction with care was associated with having a family physician (p = 0.018) and having health insurance (p = 0.041). Nevertheless, confidence in the healthcare system's ability to treat malaria effectively was significantly lower, with only 39% (148/382) receiving a positive score on the HCP index. CONCLUSION: This study provides an important insight into FISSA experience with and perception of the Alberta's healthcare system.

Intestinal Injury in Ugandan Children Hospitalized With Malaria.

BACKGROUND: Severe malaria is associated with multiple organ dysfunction syndrome (MODS), which may involve the gastrointestinal tract. METHODS: In a prospective cohort study in Uganda, we measured markers of intestinal injury (intestinal fatty-acid binding protein [I-FABP] and zonula occludens-1 [ZO-1]) and microbial translocation (lipopolysaccharide binding protein [LBP] and soluble complement of differentiation 14 [sCD14]) among children admitted with malaria. We examined their association with biomarkers of inflammation, endothelial activation, clinical signs of hypoperfusion, organ injury, and mortality. RESULTS: We enrolled 523 children (median age 1.5 years, 46% female, 7.5% mortality). Intestinal FABP was above the normal range (≥400 pg/mL) in 415 of 523 patients (79%). Intestinal FABP correlated with ZO-1 (ρ = 0.11, P = .014), sCD14 (ρ = 0.12, P = .0046) as well as markers of inflammation and endothelial activation. Higher I-FABP levels were associated with lower systolic blood pressure (ρ = -0.14, P = .0015), delayed capillary refill time (ρ = 0.17, P = .00011), higher lactate level (ρ = 0.40, P < .0001), increasing stage of acute kidney injury (ρ = 0.20, P = .0034), and coma (P < .0001). Admission I-FABP levels ≥5.6 ng/mL were associated with a 7.4-fold higher relative risk of in-hospital death (95% confidence interval, 1.4-11, P = .0016). CONCLUSIONS: Intestinal injury occurs commonly in children hospitalized with malaria and is associated with microbial translocation, systemic inflammation, tissue hypoperfusion, MODS, and fatal outcome.

Immune and endothelial activation markers and risk stratification of childhood pneumonia in Uganda: A secondary analysis of a prospective cohort study.

BACKGROUND: Despite the global burden of pneumonia, reliable triage tools to identify children in low-resource settings at risk of severe and fatal respiratory tract infection are lacking. This study assessed the ability of circulating host markers of immune and endothelial activation quantified at presentation, relative to currently used clinical measures of disease severity, to identify children with pneumonia who are at risk of death. METHODS AND FINDINGS: We conducted a secondary analysis of a prospective cohort study of children aged 2 to 59 months presenting to the Jinja Regional Hospital in Jinja, Uganda between February 2012 and August 2013, who met the Integrated Management of Childhood Illness (IMCI) diagnostic criteria for pneumonia. Circulating plasma markers of immune (IL-6, IL-8, CXCL-10/IP-10, CHI3L1, sTNFR1, and sTREM-1) and endothelial (sVCAM-1, sICAM-1, Angpt-1, Angpt-2, and sFlt-1) activation measured at hospital presentation were compared to lactate, respiratory rate, oxygen saturation, procalcitonin (PCT), and C-reactive protein (CRP) with a primary outcome of predicting 48-hour mortality. Of 805 children with IMCI pneumonia, 616 had severe pneumonia. Compared to 10 other immune and endothelial activation markers, sTREM-1 levels at presentation had the best predictive accuracy in identifying 48-hour mortality for children with pneumonia (AUROC 0.885, 95% CI 0.841 to 0.928; p = 0.03 to p < 0.001) and severe pneumonia (AUROC 0.870, 95% CI 0.824 to 0.916; p = 0.04 to p < 0.001). sTREM-1 was more strongly associated with 48-hour mortality than lactate (AUROC 0.745, 95% CI 0.664 to 0.826; p < 0.001), respiratory rate (AUROC 0.615, 95% CI 0.528 to 0.702; p < 0.001), oxygen saturation (AUROC 0.685, 95% CI 0.594 to 0.776; p = 0.002), PCT (AUROC 0.650, 95% CI 0.566 to 0.734; p < 0.001), and CRP (AUROC 0.562, 95% CI 0.472 to 0.653; p < 0.001) in cases of pneumonia and severe pneumonia. The main limitation of this study was the unavailability of radiographic imaging. CONCLUSIONS: In this cohort of Ugandan children, sTREM-1 measured at hospital presentation was a significantly better indicator of 48-hour mortality risk than other common approaches to risk stratify children with pneumonia. Measuring sTREM-1 at clinical presentation may improve the early triage, management, and outcome of children with pneumonia at risk of death. TRIAL REGISTRATION: The trial was registered at clinicaltrial.gov (NCT04726826).

Blackwater fever and acute kidney injury in children hospitalized with an acute febrile illness: pathophysiology and prognostic significance.

BACKGROUND: Acute kidney injury (AKI) and blackwater fever (BWF) are related but distinct renal complications of acute febrile illness in East Africa. The pathogenesis and prognostic significance of BWF and AKI are not well understood. METHODS: A prospective observational cohort study was conducted to evaluate the association between BWF and AKI in children hospitalized with an acute febrile illness. Secondary objectives were to examine the association of AKI and BWF with (i) host response biomarkers and (ii) mortality. AKI was defined using the Kidney Disease: Improving Global Outcomes criteria and BWF was based on parental report of tea-colored urine. Host markers of immune and endothelial activation were quantified on admission plasma samples. The relationships between BWF and AKI and clinical and biologic factors were evaluated using multivariable regression. RESULTS: We evaluated BWF and AKI in 999 children with acute febrile illness (mean age 1.7 years (standard deviation 1.06), 55.7% male). At enrollment, 8.2% of children had a history of BWF, 49.5% had AKI, and 11.1% had severe AKI. A history of BWF was independently associated with 2.18-fold increased odds of AKI (95% CI 1.15 to 4.16). When examining host response, severe AKI was associated with increased immune and endothelial activation (increased CHI3L1, sTNFR1, sTREM-1, IL-8, Angpt-2, sFlt-1) while BWF was predominantly associated with endothelial activation (increased Angpt-2 and sFlt-1, decreased Angpt-1). The presence of severe AKI, not BWF, was associated with increased risk of in-hospital death (RR, 2.17 95% CI 1.01 to 4.64) adjusting for age, sex, and disease severity. CONCLUSIONS: BWF is associated with severe AKI in children hospitalized with a severe febrile illness. Increased awareness of AKI in the setting of BWF, and improved access to AKI diagnostics, is needed to reduce disease progression and in-hospital mortality in this high-risk group of children through early implementation of kidney-protective measures.

Interleukin-18 binding protein in infants and children hospitalized with pneumonia in low-resource settings.

Pneumonia is the leading infectious cause of death in children, with especially high mortality in low- and middle-income countries. Interleukin-18 binding protein (IL-18BP) is a natural antagonist of the pro-inflammatory cytokine interleukin-18 and is elevated in numerous autoimmune conditions and infectious diseases. We conducted a prospective cohort study to determine the association between admission IL-18BP levels and clinical severity among children admitted to two hospitals in Uganda for hypoxemic pneumonia. A total of 42 children (median age of 1.2 years) were included. IL-18BP levels were higher in patients with respiratory distress, including chest indrawing (median 15 ng/mL (IQR 9.8-18) versus 4.5 ng/mL (IQR 3.8-11) without chest indrawing, P = 0.0064) and nasal flaring (median 15 ng/mL (IQR 9.7-19) versus 11 ng/mL (IQR 5.4-14) without nasal flaring, P = 0.034). IL-18BP levels were positively correlated with the composite clinical severity score, Pediatric Early Death Index for Africa (PEDIA-e, ρ = 0.46, P = 0.0020). Patients with IL-18BP > 14 ng/mL also had slower recovery times, including time to sit (median 0.69 days (IQR 0.25-1) versus 0.15 days (IQR 0.076-0.36) with IL-18BP < 14 ng/mL, P = 0.036) and time to fever resolution (median 0.63 days (IQR 0.16-2) versus 0.13 days (IQR 0-0.42), P = 0.016). In summary, higher IL-18BP levels were associated with increased disease severity and prolonged recovery times in Ugandan children with pneumonia.

Soluble T cell immunoglobulin and mucin-domain containing protein 3 in children hospitalized with pneumonia in resource-limited settings.

In a prospective cohort study of 77 children with severe pneumonia from two hospitals in Uganda, we assessed soluble T cell immunoglobulin and mucin-domain containing protein 3 (sTIM-3) levels at hospital admission and their association with pneumonia severity and subsequent mortality. sTIM-3 levels were positively correlated with the Respiratory Index of Severity in Children (RISC) (ρ = 0.35, p = 0.0017), sTIM-3 levels were higher in children who required transfer to a tertiary hospital (p = 0.014) and in fatal cases (p = 0.011). In summary, sTIM-3 is associated with disease severity and predictive of mortality in childhood pneumonia in resource-limited settings.

Implementation of solar powered oxygen delivery in a conflict zone: preliminary findings from Somalia on feasibility and usefulness.

Access to therapeutic oxygen in low-resource settings remains a significant global problem. Solar powered oxygen (SPO2) delivery is a reliable and cost-effective solution. We followed implementation research methodology to gather data on engineering parameters (remote monitoring), nurse training (before and after knowledge questionnaire), patients treated with SPO2 (descriptive case series), and qualitative user feedback (focus group discussions). In January 2021, SPO2 was installed at Hanano General Hospital in Dusamareb, Galmudug State, Somalia, in a conflict-affected region. Daily photovoltaic cell output (median 8.0 kWh, interquartile range (IQR) 2.6-14) exceeded the electrical load from up to three oxygen concentrators (median 5.0 kWh, IQR 0.90-12). Over the first six months after implementation, 114 patients (age 1 day to 89 years, 54% female) were treated for hypoxaemic illnesses, including COVID-19, pneumonia, neonatal asphyxia, asthma, and trauma. Qualitative end user feedback highlighted SPO2 acceptability. Violent conflict was identified as a contextual factor affecting local oxygen needs. We provide the preliminary findings of this implementation research study and describe the feasibility, fidelity, rapid adoption, usefulness, and acceptability of SPO2 in a low-resource setting characterized by violent conflict during the COVID-19 pandemic. Our findings demonstrated the lifesaving feasibility of SPO2 in volatile settings.

Neuroinvasive potential of human coronavirus OC43: case report of fatal encephalitis in an immunocompromised host.

Neurologic manifestations of COVID-19 include anosmia, ageusia, encephalopathy, agitation, confusion, ischemic strokes, Guillain-Barré syndrome, seizures, and hemorrhagic encephalitis. Although mechanisms of central nervous system (CNS) injury are likely diverse, direct viral invasion of the CNS has been demonstrated in case reports. Neurotropism of human coronaviruses (HCoVs) is therefore of great interest in the context of the COVID-19 pandemic. Here we present an autopsy-proven case of fatal human coronavirus (HCoV)-OC43 encephalitis in an infant with aplastic thymus and chronic T-cell lymphopenia. Clinicians should remain alert to the possibility of direct CNS invasion by human coronaviruses, including the novel pandemic SARS-CoV-2.

A feasibility study evaluating a reservoir storage system for continuous oxygen delivery for children with hypoxemia in Kenya.

BACKGROUND: Supplemental oxygen is an essential treatment for childhood pneumonia but is often unavailable in low-resource settings or unreliable due to frequent and long-lasting power outages. We present a novel medium pressure reservoir (MPR) which delivers continuous oxygen to pediatric patients through power outages. METHODS: An observational case series pilot study assessing the capacity, efficacy and user appraisal of a novel MPR device for use in low-resource pediatric wards. We designed and tested a MPR in a controlled preclinical setting, established feasibility of the device in two rural Kenyan hospitals, and sought user feedback and satisfaction using a standardized questionnaire. RESULTS: Preclinical data showed that the MPR was capable of bridging power outages and delivering a continuous flow of oxygen to a simulated patient. The MPR was then deployed for clinical testing in nine pediatric patients at Ahero and Suba Hospitals. Power was unavailable for 2% of the total time observed due to 11 power outages (median 4.6 min, IQR 3.6-13.0 min) that occurred during treatment with the MPR. Oxygen flowrates remained constant across all 11 power outages. Feedback on the MPR was uniformly positive; all respondents indicated that the MPR was easy to use and provided clinically significant help to their patients. CONCLUSION: We present a MPR oxygen delivery device that has the potential to mitigate power insecurity and improve the standard of care for hypoxemic pediatric patients in resource-limited settings.

Clinical Correlates of Human Immunodeficiency Virus-1 (HIV-1) DNA and Inducible HIV-1 RNA Reservoirs in Peripheral Blood in Children With Perinatally Acquired HIV-1 Infection With Sustained Virologic Suppression for at Least 5 Years.

BACKGROUND: The Early Pediatric Initiation Canada Child Cure Cohort (EPIC4) study is a prospective, multicenter, Canadian cohort study investigating human immunodeficiency virus-1 (HIV-1) reservoirs, chronic inflammation, and immune responses in children with perinatally acquired HIV-1 infection. The focus of this report is HIV-1 reservoirs and correlates in the peripheral blood of children who achieved sustained virologic suppression (SVS) for ≥5 years. METHODS: HIV-1 reservoirs were determined by measuring HIV-1 DNA in peripheral blood mononuclear cells and inducible cell-free HIV-1 RNA in CD4+ T-cells by a prostratin analogue stimulation assay. HIV serology was quantified by signal-to-cutoff ratio (S/CO). RESULTS: Of 228 enrolled participants, 69 achieved SVS for ≥5 years. HIV-1 DNA, inducible cell-free HIV-1 RNA, and S/COs correlated directly with the age of effective combination antiretroviral therapy (cART) initiation (P < .001, P = .036, and P < .001, respectively) and age when SVS was achieved (P = .002, P = .038, and P < .001, respectively) and inversely with the proportion of life spent on effective cART (P < .001, P = .01, and P < .001, respectively) and proportion of life spent with SVS (P < .001, P = .079, and P < .001, respectively). Inducible cell-free HIV-1 RNA correlated with HIV-1 DNA, most particularly in children with SVS, without virologic blips, that was achieved with the first cART regimen initiated prior to 6 months of age (rho = 0.74; P = .037) or later (rho = 0.87; P < .001). S/COs correlated with HIV-1 DNA (P = .003), but less so with inducible cell-free HIV-1 RNA (P = .09). CONCLUSIONS: The prostratin analogue stimulation assay, with its lower blood volume requirement, could be a valuable method for evaluating inducible HIV-1 reservoirs in children. Standard commercial HIV serology may be a practical initial indirect measure of reservoir size in the peripheral blood of children with perinatally acquired HIV-1 infection.

Dysregulation of angiopoietin-Tie-2 axis in ugandan children hospitalized with pneumonia.

OBJECTIVE: Pneumonia is the leading cause of death in children under 5, with the highest burden in resource-limited countries. Endothelial activation occurs in pneumonia and can be assessed using quantitative levels of biomarkers angiopoietin (Ang)-1 and Ang-2. We examined admission levels of Ang-1 and Ang-2 in pediatric pneumonia and their association with disease severity and outcome. METHODS: Prospective cohort study of children with hypoxemic pneumonia admitted to two hospitals in Uganda. Clinical, radiographic, and microbiologic characteristics were measured at admission. Disease severity was assessed using the Respiratory Index of Severity in Children (RISC). Plasma levels of Ang-1 and Ang-2 were quantified by enzyme-linked immunosorbent assay. Vital signs, oxygen supplementation, and mortality were assessed prospectively. RESULTS: We included 65 patients (43% female) with median age 19 months (IQR 8-24). Admission Ang-2/Ang-1 ratio directly correlated with RISC (ρ = 0.32, p = 0.008) and lactate level (ρ = 0.48, p < 0.001). Ang-2/Ang-1 ratio was higher in pneumococcal pneumonia than viral RTI (0.19 [IQR: 0.076-0.54] vs. 0.078 [IQR: 0.027-0.11]; p = 0.03). Elevated Ang-2/Ang-1 ratio (>0.084) was associated with prolonged tachypnea (HR 0.50 (95%CI 0.29-0.87), p = 0.02), fever (HR 0.56 (95%CI 0.33 to 0.96), p = 0.02), longer duration of oxygen therapy (HR 0.59 (95%CI 0.35-0.99), p = 0.04), and hospital stay (HR 0.43 (95%CI 0.25-0.74), p = 0.001). The Ang-2/Ang-1 ratio at admission was higher in fatal cases relative to survivors (0.36 [IQR: 0.17-0.58] vs. 0.077 [IQR: 0.025-0.19]; p = 0.05) CONCLUSION: Endothelial activation in hypoxemic pediatric pneumonia, reflected by high plasma Ang-2/Ang-1 ratio, is associated with disease severity, prolonged recovery time, and mortality.

Efficacy and safety of oxygen-sparing nasal reservoir cannula for treatment of pediatric hypoxemic pneumonia in Uganda: a pilot randomized clinical trial.

BACKGROUND: Oxygen is an essential therapy for hypoxemia but is scarce in low-income settings. Oxygen conserving devices optimize delivery, but to date have been designed for adults in high-income settings. Here we present the development and clinical pilot study of an oxygen-sparing nasal reservoir cannula (OSNRC) for pediatric use in low-income settings. METHODS: (1) Pre-clinical development of a novel OSNRC using a simulated respiratory circuit with metabolic simulator and anatomically accurate face-airway models. Simulated breathing waveforms were designed based on airway resistance, lung compliance, respiratory rate, and tidal volume of spontaneous breathing for three disease conditions. (2) Pilot, randomized, controlled, non-blinded, cross-over study of the OSNRC vs standard nasal cannula (SNC) among children hospitalized with hypoxemic pneumonia in Uganda. Eight children were randomized to OSNRC followed by SNC, and eight were randomized to SNC followed by OSNRC. RESULTS: The laboratory simulation showed that the OSNRC provided the same or higher fraction of inspired oxygen at approximately 2.5-times lower flow rate compared to SNC. The flow savings ratio exhibited a linear relationship with the OSNRC volume to tidal volume ratio with a slope that varied with breathing waveforms. The range of performance from different breathing waveforms defined a performance envelope of the OSNRC. Two mask sizes (30 mL and 50 mL) provided sufficient coverage for patients between the 3rd and 97th percentile in our targeted age range. In the clinical pilot study, the rise in capillary blood pCO2 was similar in the OSNRC and SNC groups, suggesting that the OSNRC was not associated with CO2 retention. There were no significant differences between OSNRC and SNC with respect to clinical adverse events, lactate levels, pH, and SpO2. The OSNRC group had a higher mean SpO2 than the SNC group (adjusted mean difference, 1.4, 95% confidence interval 1.1 to 1.8), showing oxygen delivery enhancement. CONCLUSION: The OSNRC enhances oxygen delivery without causing CO2 retention and appears to be well-tolerated by pediatric patients. If safety, efficacy and tolerability are confirmed in larger trials, this device has the potential to optimize oxygen delivery in children in low-resource settings, reducing the global burden of pediatric pneumonia. TRIAL REGISTRATION: The trial was retrospectively registered (International Standard Registered Clinical/Social Study Number (ISRCTN): 15216845 ; Date of registration: 15 July 2020).

Anemia and transfusion requirements among Ugandan children with severe malaria treated with intravenous artesunate.

Parenteral artesunate for the treatment of severe malaria in non-immune travelers is associated with late-onset hemolysis. In children in sub-Saharan Africa, the hematologic effects of malaria and artesunate are less well documented. Here we report a prospective case series of 91 children with severe malaria treated with parenteral artesunate, managed at a resource-poor hospital in Africa, with longitudinal data on hemoglobin (Hb), lactate dehydrogenase (LDH), haptoglobin, and erythrocyte morphology. The median (range) age was 2 (1-8) years and 43 (47%) were female. The median (IQR) admission Hb level was 69 (55-78) g/L and 20 patients (22%) had severe malarial anemia (Hb < 50 g/L). During hospitalization, 69 patients (76%) received one or more blood transfusions. Fatal outcome in 8 patients was associated with severe anemia in 6/8 cases. Follow-up Hb measurement was performed on 35 patients (38%) at day 14 after initial hospital admission; the remaining patients had no clinical evidence of anemia at the follow-up visit. The convalescent Hb was median (range) 90 (60-138) g/L, which was significantly higher than the paired admission levels (median increase +28 g/L, p < .001). Evidence of hemolysis (elevated LDH and low haptoglobin) was common at admission and improved by day 14. No patient met the standardized definition of post-artemisinin delayed hemolysis (PADH). In this cohort of young children with severe malaria treated with artesunate, anemia was common at admission, required one or more transfusions in a majority of patients, and markers of hemolysis had normalized by day 14.

Clinical Outcomes of Submicroscopic Infections and Correlates of Protection of VAR2CSA Antibodies in a Longitudinal Study of Pregnant Women in Colombia.

Malaria in pregnancy can cause serious adverse outcomes for the mother and the fetus. However, little is known about the effects of submicroscopic infections (SMIs) in pregnancy, particularly in areas where Plasmodium falciparum and Plasmodium vivax cocirculate. A cohort of 187 pregnant women living in Puerto Libertador in northwest Colombia was followed longitudinally from recruitment to delivery. Malaria was diagnosed by microscopy, reverse transcription-quantitative PCR (RT-qPCR), and placental histopathology. Gestational age, hemoglobin concentration, VAR2CSA-specific IgG levels, and adhesion-blocking antibodies were measured during pregnancy. Statistical analyses were performed to evaluate the impact of SMIs on birth weight and other delivery outcomes. Twenty-five percent of women (45/180) were positive for SMIs during pregnancy. Forty-seven percent of infections (21/45) were caused by P. falciparum, 33% were caused by P. vivax, and 20% were caused by mixed Plasmodium spp. Mixed infections of P. falciparum and P. vivax were associated with lower gestational age at delivery (P = 0.0033), while other outcomes were normal. Over 60% of women had antibodies to VAR2CSA, and there was no difference in antibody levels between those with and without SMIs. The anti-adhesion function of these antibodies was associated with protection from SMI-related anemia at delivery (P = 0.0086). SMIs occur frequently during pregnancy, and while mixed infections of both P. falciparum and P. vivax were not associated with a decrease in birth weight, they were associated with significant risk of preterm birth. We propose that the lack of adverse delivery outcomes is due to functional VAR2CSA antibodies that can protect pregnant women from SMI-related anemia.

Estradiol Levels Are Altered in Human Immunodeficiency Virus-Infected Pregnant Women Randomized to Efavirenz-Versus Lopinavir/Ritonavir-Based Antiretroviral Therapy.

Background: Combination antiretroviral therapy (cART) use in pregnancy has been associated with hormonal dysregulation. We performed a secondary retrospective analysis of longitudinal progesterone and estradiol levels in pregnancy using specimens from the Protease Inhibitors to Reduce Malaria Morbidity in HIV-infected Pregnant Women study, which randomized Ugandan human immunodeficiency virus (HIV)-infected ART-naive women to initiate either lopinavir/ritonavir (LPV/r)-based or efavirenz (EFV)-based cART. Methods: Three hundred twenty-six women (160 randomized to the EFV arm and 166 women to the LPV/r arm) with at least 1 plasma sample collected during pregnancy were included. Enrollment samples collected prior to cART initiation were used as a cART-naive comparator group. Hormone levels were quantified by enzyme-linked immunosorbent assay. Results: Estradiol levels were differentially affected by the 2 cART regimens. Exposure to LPV/r was associated with an increase in estradiol (P < .0001), whereas exposure to EFV was associated with a decrease in estradiol (P < .0001), relative to the cART-naive gestationally matched comparator group. Lower estradiol levels correlated with small for gestational age (SGA) (P = .0019) and low birth weight (P = .019) in the EFV arm, while higher estradiol levels correlated with SGA in the LPV/r arm (P = .027). Although progesterone levels were similar between treatment arms, we observed an association between SGA and lower progesterone in the LPV/r arm (P = .04). No association was observed between hormone levels and preterm birth in either arm. Levels of progesterone and estradiol were lower in cases of stillbirth, and levels of both hormones declined immediately prior to stillbirth in 5 of 8 cases. Conclusions: Combination ART regimens differentially affect estradiol levels in pregnancy, a hormone critical to the maintenance of a healthy pregnancy. Identifying cART regimens that minimize perinatal HIV transmission without contributing to hormonal dysregulation represents an urgent public health priority. Clinical Trials Registration: NCT00993031.

Multiple Administrations of Gadobutrol in the Pediatric Brain: No Change in T1 Signal at MRI.

Purpose To determine whether multiple doses of gadobutrol increase the T1 signal intensity in the brains of children. Materials and Methods This retrospective imaging study evaluated 91 children (median age, 5.4 years; age range, 0-17 years) with brain tumors who underwent five or more MR brain examinations at a single institution. A subgroup of 46 patients received five or more administrations of gadobutrol (0.1 mmol/kg) and underwent follow-up MRI. T1 signal intensity in the globus pallidus and dentate nucleus was measured at the first to sixth unenhanced MR brain examination in these children. Globus pallidus-to-corpus callosum and dentate nucleus-to-corpus callosum signal intensity ratios were analyzed by linear mixed-effect analysis. Subgroup analysis was performed for six children who underwent 14 or more administrations of gadobutrol. Results The globus pallidus-to-corpus callosum ratio increased with patient age (absolute change, 0.0052 per year; 95% confidence interval: 0.0033, 0.0071; P < .0001). There was no change in the dentate nucleus-to-corpus callosum ratio with age (P = .30). Among 46 children who received five or more doses of gadobutrol (median dose, 11 mL; range, 3.9-31 mL), there was no change in signal intensity ratio of the globus pallidus (P = .17) or dentate nucleus (P = .44). Among six children who underwent more than 14 administrations of gadobutrol (median dose, 64 mL; range, 40-91 mL) there was no change in signal intensity ratio of the globus pallidus (P = .15) or dentate nucleus (P = .50). Conclusion No increase in T1-weighted signal intensity ratio was observed in the globus pallidus or dentate nucleus after the administration of at least five doses of gadobutrol. © RSNA, 2018 Online supplemental material is available for this article.