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.

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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.

Background: The radiographic assessment for lung edema (RALE) score has an association with mortality in patients with acute respiratory distress syndrome (ARDS). It is uncertain whether the RALE scores at the start of invasive ventilation or changes thereof in the next days have prognostic capacities in patients with COVID-19 ARDS.Aims and Objectives: To determine the prognostic capacity of the RALE score for mortality and duration of invasive ventilation in patients with COVID-19 ARDS.Methods: An international multicenter observational study included consecutive patients from 6 ICUs. Trained observers scored the first available chest X-ray (CXR) obtained within 48 h after the start of invasive ventilation (“baseline CXR”) and each CXRs thereafter up to day 14 (“follow-up CXR”). The primary endpoint was mortality at day 90. The secondary endpoint was the number of days free from the ventilator and alive at day 28 (VFD-28).Results: A total of 350 CXRs were scored in 139 patients with COVID-19 ARDS. The RALE score of the baseline CXR was high and was not different between survivors and non-survivors (33 [24–38] vs. 30 [25–38], P = 0.602). The RALE score of the baseline CXR had no association with mortality (hazard ratio [HR], 1.24 [95% CI 0.88–1.76]; P = 0.222; area under the receiver operating characteristic curve (AUROC) 0.50 [0.40–0.60]). A change in the RALE score over the first 14 days of invasive ventilation, however, had an independent association with mortality (HR, 1.03 [95% CI 1.01–1.05]; P &lt; 0.001). When the event of death was considered, there was no significant association between the RALE score of the baseline CXR and the probability of being liberated from the ventilator (HR 1.02 [95% CI 0.99–1.04]; P = 0.08).Conclusion: In this cohort of patients with COVID-19 ARDS, with high RALE scores of the baseline CXR, the RALE score of the baseline CXR had no prognostic capacity, but an increase in the RALE score in the next days had an association with higher mortality.

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Management of patients with severe or critical COVID-19 is mainly modeled after care for patients with severe pneumonia or acute respiratory distress syndrome (ARDS) from other causes, and these recommendations are based on evidence that often originates from investigations in resource-rich intensive care units located in high-income countries. Often, it is impractical to apply these recommendations to resource-restricted settings, particularly in low-and middle-income countries (LMICs). We report on a set of pragmatic recommendations for acute respiratory failure and mechanical ventilation management in patients with severe/critical COVID-19 in LMICs. We suggest starting supplementary oxygen when SpO 2 is persistently lower than 94%. We recommend supplemental oxygen to keep SpO 2 at 88-95% and suggest higher targets in settings where continuous pulse oximetry is not available but intermittent pulse oximetry is. We suggest a trial of awake prone positioning in patients who remain hypoxemic; however, this requires close monitoring, and clear failure and escalation criteria. In places with an adequate number and trained staff, the strategy seems safe. We recommend to intubate based on signs of respiratory distress more than on refractory hypoxemia alone, and we recommend close monitoring for respiratory worsening and early intubation if worsening occurs. We recommend low-tidal volume ventilation combined with FiO 2 and positive end-expiratory pressure (PEEP) management based on a high FiO 2 /low PEEP table. We recommend against using routine recruitment maneuvers, unless as a rescue therapy in refractory hypoxemia, and we recommend using prone positioning for 12-16 hours in case of refractory hypoxemia (PaO 2 / FiO 2 < 150 mmHg, FiO 2 ³ 0.6 and PEEP ³ 10 cmH 2 O) in intubated patients as standard in ARDS patients. We also recommend against sharing one ventilator for multiple patients. We recommend daily assessments for readiness for weaning by a low-level pressure support and recommend against using a T-piece trial because of aerosolization risk.

Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and middle-income countries is needed. NDV-HXP-S is an inactivated egg-based Newcastle disease virus vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is being developed in Thailand, Vietnam, and Brazil; herein are initial results from Thailand. This phase 1 stage of a randomised, dose-escalation, observer-blind, placebo-controlled, phase 1/2 trial was conducted at the Vaccine Trial Centre, Mahidol University (Bangkok). Healthy adults aged 18-59 years, non-pregnant and negative for SARS-CoV-2 antibodies were eligible. Participants were block randomised to receive one of six treatments by intramuscular injection twice, 28 days apart: 1 microgram (mcg) +/- CpG1018 (a toll-like receptor 9 agonist), 3 mcg +/- CpG1018, 10 mcg, or placebo. Participants and personnel assessing outcomes were masked to treatment. The primary outcomes were solicited and spontaneously reported adverse events (AEs) during 7 and 28 days after each vaccination, respectively. Secondary outcomes were immunogenicity measures (anti-S IgG and pseudotyped virus neutralisation). An interim analysis assessed safety at day 57 in treatment-exposed individuals and immunogenicity through day 43 per protocol. ClinicalTrials.gov (NCT04764422). Between March 20 and April 23, 2021, 377 individuals were screened and 210 were enrolled (35 per group); all received dose one; five missed dose two. The most common solicited AEs among vaccinees, all predominantly mild, were injection site pain (<63%), fatigue (<35%), headache (<32%), and myalgia (<32%). The proportion reporting a vaccine-related AE ranged from 5.7% to 17.1% among vaccine groups and was 2.9% in controls; there was no vaccine-related serious adverse event. The immunogenicity of the 10 mcg formulation ranked best, followed by 3 mcg+CpG1018, 3 mcg, 1 mcg+CpG1018, and 1 mcg formulations. On day 43, the geometric mean concentrations of 50% neutralising antibody ranged from 122.23 IU/mL (1 mcg, 95% CI 86.40-172.91) to 474.35 IU/mL (10 mcg, 95% CI 320.90-701.19), with 93.9% to 100% of vaccine groups attaining a => 4-fold increase over baseline. NDV-HXP-S had an acceptable safety profile and potent immunogenicity. The 3 mcg and 3 mcg+CpG1018 formulations advanced to phase 2.