Glucose-6-Phosphate Dehydrogenase (G6PD) Measurement Using Biosensors by Community-Based Village Malaria Workers and Hospital Laboratory Staff in Cambodia: A Quantitative Study.

Vivax malaria can relapse after an initial infection due to dormant liver stages of the parasite. Radical cure can prevent relapses but requires the measurement of glucose-6-phosphate dehydrogenase enzyme (G6PD) activity to identify G6PD-deficient patients at risk of drug-induced haemolysis. In the absence of reliable G6PD testing, vivax patients are denied radical curative treatment in many places, including rural Cambodia. A novel Biosensor, 'G6PD Standard' (SD Biosensor, Republic of Korea; Biosensor), can measure G6PD activity at the point of care. The objectives of this study were to compare the G6PD activity readings using Biosensors by village malaria workers (VMWs) and hospital-based laboratory technicians (LTs), and to compare the G6PD deficiency categorization recommended by the Biosensor manufacturer with categories derived from a locally estimated adjusted male median (AMM) in Kravanh district, Cambodia. Participants were enrolled between 2021 and 2022 in western Cambodia. Each of the 28 VMWs and 5 LTs received a Biosensor and standardized training on its use. The G6PD activities of febrile patients identified in the community were measured by VMWs; in a subset, a second reading was done by LTs. All participants were tested for malaria by rapid diagnostic test (RDT). The adjusted male median (AMM) was calculated from all RDT-negative participants and defined as 100% G6PD activity. VMWs measured activities in 1344 participants. Of that total, 1327 (98.7%) readings were included in the analysis, and 68 of these had a positive RDT result. We calculated 100% activity as 6.4 U/gHb (interquartile range: 4.5 to 7.8); 9.9% (124/1259) of RDT-negative participants had G6PD activities below 30%, 15.2% (191/1259) had activities between 30% and 70%, and 75.0% (944/1259) had activities greater than 70%. Repeat measurements among 114 participants showed a significant correlation of G6PD readings (rs = 0.784, p < 0.001) between VMWs and LTs. Based on the manufacturer's recommendations, 285 participants (21.5%) had less than 30% activity; however, based on the AMM, 132 participants (10.0%) had less than 30% activity. The G6PD measurements by VMWs and LTs were similar. With the provisions of training, supervision, and monitoring, VMWs could play an important role in the management of vivax malaria, which is critical for the rapid elimination of malaria regionally. Definitions of deficiency based on the manufacturer's recommendations and the population-specific AMM differed significantly, which may warrant revision of these recommendations.

Pharmacometrics of high-dose ivermectin in early COVID-19 from an open label, randomized, controlled adaptive platform trial (PLATCOV).

Background: There is no generally accepted methodology for in vivo assessment of antiviral activity in SARS-CoV-2 infections. Ivermectin has been recommended widely as a treatment of COVID-19, but whether it has clinically significant antiviral activity in vivo is uncertain. Methods: In a multicentre open label, randomized, controlled adaptive platform trial, adult patients with early symptomatic COVID-19 were randomized to one of six treatment arms including high-dose oral ivermectin (600 µg/kg daily for 7 days), the monoclonal antibodies casirivimab and imdevimab (600 mg/600 mg), and no study drug. The primary outcome was the comparison of viral clearance rates in the modified intention-to-treat population. This was derived from daily log10 viral densities in standardized duplicate oropharyngeal swab eluates. This ongoing trial is registered at https://clinicaltrials.gov/ (NCT05041907). Results: Randomization to the ivermectin arm was stopped after enrolling 205 patients into all arms, as the prespecified futility threshold was reached. Following ivermectin, the mean estimated rate of SARS-CoV-2 viral clearance was 9.1% slower (95% confidence interval [CI] -27.2% to +11.8%; n=45) than in the no drug arm (n=41), whereas in a preliminary analysis of the casirivimab/imdevimab arm it was 52.3% faster (95% CI +7.0% to +115.1%; n=10 (Delta variant) vs. n=41). Conclusions: High-dose ivermectin did not have measurable antiviral activity in early symptomatic COVID-19. Pharmacometric evaluation of viral clearance rate from frequent serial oropharyngeal qPCR viral density estimates is a highly efficient and well-tolerated method of assessing SARS-CoV-2 antiviral therapeutics in vitro. Funding: 'Finding treatments for COVID-19: A phase 2 multi-centre adaptive platform trial to assess antiviral pharmacodynamics in early symptomatic COVID-19 (PLAT-COV)' is supported by the Wellcome Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics Accelerator. Clinical trial number: NCT05041907.

Facilitating Safe Discharge Through Predicting Disease Progression in Moderate Coronavirus Disease 2019 (COVID-19): A Prospective Cohort Study to Develop and Validate a Clinical Prediction Model in Resource-Limited Settings.

BACKGROUND: In locations where few people have received coronavirus disease 2019 (COVID-19) vaccines, health systems remain vulnerable to surges in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Tools to identify patients suitable for community-based management are urgently needed. METHODS: We prospectively recruited adults presenting to 2 hospitals in India with moderate symptoms of laboratory-confirmed COVID-19 to develop and validate a clinical prediction model to rule out progression to supplemental oxygen requirement. The primary outcome was defined as any of the following: SpO2 < 94%; respiratory rate > 30 BPM; SpO2/FiO2 < 400; or death. We specified a priori that each model would contain three clinical parameters (age, sex, and SpO2) and 1 of 7 shortlisted biochemical biomarkers measurable using commercially available rapid tests (C-reactive protein [CRP], D-dimer, interleukin 6 [IL-6], neutrophil-to-lymphocyte ratio [NLR], procalcitonin [PCT], soluble triggering receptor expressed on myeloid cell-1 [sTREM-1], or soluble urokinase plasminogen activator receptor [suPAR]), to ensure the models would be suitable for resource-limited settings. We evaluated discrimination, calibration, and clinical utility of the models in a held-out temporal external validation cohort. RESULTS: In total, 426 participants were recruited, of whom 89 (21.0%) met the primary outcome; 257 participants comprised the development cohort, and 166 comprised the validation cohort. The 3 models containing NLR, suPAR, or IL-6 demonstrated promising discrimination (c-statistics: 0.72-0.74) and calibration (calibration slopes: 1.01-1.05) in the validation cohort and provided greater utility than a model containing the clinical parameters alone. CONCLUSIONS: We present 3 clinical prediction models that could help clinicians identify patients with moderate COVID-19 suitable for community-based management. The models are readily implementable and of particular relevance for locations with limited resources.

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.

High Mobility Group Box 1 and Interleukin 6 at Intensive Care Unit Admission as Biomarkers in Critically Ill COVID-19 Patients.

Exuberant inflammation manifesting as a "cytokine storm" has been suggested as a central feature in the pathogenesis of severe coronavirus disease 2019 (COVID-19). This study investigated two prognostic biomarkers, the high mobility group box 1 (HMGB1) and interleukin-6 (IL-6), in patients with severe COVID-19 at the time of admission in the intensive care unit (ICU). Of 60 ICU patients with COVID-19 enrolled and analyzed in this prospective cohort study, 48 patients (80%) were alive at ICU discharge. HMGB1 and IL-6 plasma levels at ICU admission were elevated compared with a healthy control, both in ICU nonsurvivors and ICU survivors. HMGB1 and IL-6 plasma levels were higher in patients with a higher Sequential Organ Failure Assessment (SOFA) score (> 10), and the presence of septic shock or acute kidney injury. HMGB1 and IL-6 plasma levels were also higher in patients with a poor oxygenation status (PaO2/FiO2 < 150 mm Hg) and a longer duration of ventilation (> 7 days). Plasma HMGB1 and IL-6 levels at ICU admission also correlated with other prognostic markers, including the maximum neutrophil/lymphocyte ratio, D-dimer levels, and C-reactive protein levels. Plasma HMGB1 and IL-6 levels at ICU admission predicted ICU mortality with comparable accuracy to the SOFA score and the COVID-GRAM risk score. Higher HMGB1 and IL-6 were not independently associated with ICU mortality after adjustment for age, gender, and comorbidities in multivariate analysis models. In conclusion, plasma HMGB1 and IL6 at ICU admission may serve as prognostic biomarkers in critically ill COVID-19 patients.

Awake Proning as an Adjunctive Therapy for Refractory Hypoxemia in Non-Intubated Patients with COVID-19 Acute Respiratory Failure: Guidance from an International Group of Healthcare Workers.

Non-intubated patients with acute respiratory failure due to COVID-19 could benefit from awake proning. Awake proning is an attractive intervention in settings with limited resources, as it comes with no additional costs. However, awake proning remains poorly used probably because of unfamiliarity and uncertainties regarding potential benefits and practical application. To summarize evidence for benefit and to develop a set of pragmatic recommendations for awake proning in patients with COVID-19 pneumonia, focusing on settings where resources are limited, international healthcare professionals from high and low- and middle-income countries (LMICs) with known expertise in awake proning were invited to contribute expert advice. A growing number of observational studies describe the effects of awake proning in patients with COVID-19 pneumonia in whom hypoxemia is refractory to simple measures of supplementary oxygen. Awake proning improves oxygenation in most patients, usually within minutes, and reduces dyspnea and work of breathing. The effects are maintained for up to 1 hour after turning back to supine, and mostly disappear after 6-12 hours. In available studies, awake proning was not associated with a reduction in the rate of intubation for invasive ventilation. Awake proning comes with little complications if properly implemented and monitored. Pragmatic recommendations including indications and contraindications were formulated and adjusted for resource-limited settings. Awake proning, an adjunctive treatment for hypoxemia refractory to supplemental oxygen, seems safe in non-intubated patients with COVID-19 acute respiratory failure. We provide pragmatic recommendations including indications and contraindications for the use of awake proning in LMICs.

Operationalisation of the Randomized Embedded Multifactorial Adaptive Platform for COVID-19 trials in a low and lower-middle income critical care learning health system.

The Randomized Embedded Multifactorial Adaptive Platform (REMAP-CAP) adapted for COVID-19) trial is a global adaptive platform trial of hospitalised patients with COVID-19. We describe implementation in three countries under the umbrella of the Wellcome supported Low and Middle Income Country (LMIC) critical  care network: Collaboration for Research, Implementation and Training in Asia (CCA). The collaboration sought to overcome known barriers to multi centre-clinical trials in resource-limited settings. Methods described focused on six aspects of implementation: i, Strengthening an existing community of practice; ii, Remote study site recruitment, training and support; iii, Harmonising the REMAP CAP- COVID trial with existing care processes; iv, Embedding REMAP CAP- COVID case report form into the existing CCA registry platform, v, Context specific adaptation and data management; vi, Alignment with existing pandemic and critical care research in the CCA. Methods described here may enable other LMIC sites to participate as equal partners in international critical care trials of urgent public health importance, both during this pandemic and beyond.

Leveraging a Cloud-Based Critical Care Registry for COVID-19 Pandemic Surveillance and Research in Low- and Middle-Income Countries.

The COVID-19 pandemic has revealed limitations in real-time surveillance needed for responsive health care action in low- and middle-income countries (LMICs). The Pakistan Registry for Intensive CarE (PRICE) was adapted to enable International Severe Acute Respiratory and emerging Infections Consortium (ISARIC)-compliant real-time reporting of severe acute respiratory infection (SARI). The cloud-based common data model and standardized nomenclature of the registry platform ensure interoperability of data and reporting between regional and global stakeholders. Inbuilt analytics enable stakeholders to visualize individual and aggregate epidemiological, clinical, and operational data in real time. The PRICE system operates in 5 of 7 administrative regions of Pakistan. The same platform supports acute and critical care registries in eleven countries in South Asia and sub-Saharan Africa. ISARIC-compliant SARI reporting was successfully implemented by leveraging the existing PRICE infrastructure in all 49 member intensive care units (ICUs), enabling clinicians, operational leads, and established stakeholders with responsibilities for coordinating the pandemic response to access real-time information on suspected and confirmed COVID-19 cases (N=592 as of May 2020) via secure registry portals. ICU occupancy rates, use of ICU resources, mechanical ventilation, renal replacement therapy, and ICU outcomes were reported through registry dashboards. This information has facilitated coordination of critical care resources, health care worker training, and discussions on treatment strategies. The PRICE network is now being recruited to international multicenter clinical trials regarding COVID-19 management, leveraging the registry platform. Systematic and standardized reporting of SARI is feasible in LMICs. Existing registry platforms can be adapted for pandemic research, surveillance, and resource planning.

Respiratory Support in COVID-19 Patients, with a Focus on Resource-Limited Settings.

The ongoing novel coronavirus disease (COVID-19) pandemic is threatening the global human population, including in countries with resource-limited health facilities. Severe bilateral pneumonia is the main feature of severe COVID-19, and adequate ventilatory support is crucial for patient survival. Although our knowledge of the disease is still rapidly increasing, this review summarizes current guidance on the best provision of ventilatory support, with a focus on resource-limited settings. Key messages include that supplemental oxygen is a first essential step for the treatment of severe COVID-19 patients with hypoxemia and should be a primary focus in resource-limited settings where capacity for invasive ventilation is limited. Oxygen delivery can be increased by using a non-rebreathing mask and prone positioning. The presence of only hypoxemia should in general not trigger intubation because hypoxemia is often remarkably well tolerated. Patients with fatigue and at risk for exhaustion, because of respiratory distress, will require invasive ventilation. In these patients, lung protective ventilation is essential. Severe pneumonia in COVID-19 differs in some important aspects from other causes of severe pneumonia or acute respiratory distress syndrome, and limiting the positive end-expiratory pressure level on the ventilator may be important. This ventilation strategy might reduce the currently very high case fatality rate of more than 50% in invasively ventilated COVID-19 patients.