Inter-rater reliability and prognostic value of baseline Radiographic Assessment of Lung Edema (RALE) scores in observational cohort studies of inpatients with COVID-19.

OBJECTIVES: To reliably quantify the radiographic severity of COVID-19 pneumonia with the Radiographic Assessment of Lung Edema (RALE) score on clinical chest X-rays among inpatients and examine the prognostic value of baseline RALE scores on COVID-19 clinical outcomes. SETTING: Hospitalised patients with COVID-19 in dedicated wards and intensive care units from two different hospital systems. PARTICIPANTS: 425 patients with COVID-19 in a discovery data set and 415 patients in a validation data set. PRIMARY AND SECONDARY OUTCOMES: We measured inter-rater reliability for RALE score annotations by different reviewers and examined for associations of consensus RALE scores with the level of respiratory support, demographics, physiologic variables, applied therapies, plasma host-response biomarkers, SARS-CoV-2 RNA load and clinical outcomes. RESULTS: Inter-rater agreement for RALE scores improved from fair to excellent following reviewer training and feedback (intraclass correlation coefficient of 0.85 vs 0.93, respectively). In the discovery cohort, the required level of respiratory support at the time of CXR acquisition (supplemental oxygen or non-invasive ventilation (n=178); invasive-mechanical ventilation (n=234), extracorporeal membrane oxygenation (n=13)) was significantly associated with RALE scores (median (IQR): 20.0 (14.1-26.7), 26.0 (20.5-34.0) and 44.5 (34.5-48.0), respectively, p<0.0001). Among invasively ventilated patients, RALE scores were significantly associated with worse respiratory mechanics (plateau and driving pressure) and gas exchange metrics (PaO2/FiO2 and ventilatory ratio), as well as higher plasma levels of IL-6, soluble receptor of advanced glycation end-products and soluble tumour necrosis factor receptor 1 (p<0.05). RALE scores were independently associated with 90-day survival in a multivariate Cox proportional hazards model (adjusted HR 1.04 (1.02-1.07), p=0.002). We replicated the significant associations of RALE scores with baseline disease severity and mortality in the independent validation data set. CONCLUSIONS: With a reproducible method to measure radiographic severity in COVID-19, we found significant associations with clinical and physiologic severity, host inflammation and clinical outcomes. The incorporation of radiographic severity assessments in clinical decision-making may provide important guidance for prognostication and treatment allocation in COVID-19.

Radiographic Assessment of Lung Edema (RALE) Scores are Highly Reproducible and Prognostic of Clinical Outcomes for Inpatients with COVID-19.

INTRODUCTION: Chest imaging is necessary for diagnosis of COVID-19 pneumonia, but current risk stratification tools do not consider radiographic severity. We quantified radiographic heterogeneity among inpatients with COVID-19 with the Radiographic Assessment of Lung Edema (RALE) score on Chest X-rays (CXRs). METHODS: We performed independent RALE scoring by ≥2 reviewers on baseline CXRs from 425 inpatients with COVID-19 (discovery dataset), we recorded clinical variables and outcomes, and measured plasma host-response biomarkers and SARS-CoV-2 RNA load from subjects with available biospecimens. RESULTS: We found excellent inter-rater agreement for RALE scores (intraclass correlation co-efficient=0.93). The required level of respiratory support at the time of baseline CXRs (supplemental oxygen or non-invasive ventilation [n=178]; invasive-mechanical ventilation [n=234], extracorporeal membrane oxygenation [n=13]) was significantly associated with RALE scores (median [interquartile range]: 20.0[14.1-26.7], 26.0[20.5-34.0] and 44.5[34.5-48.0], respectively, p<0.0001). Among invasively-ventilated patients, RALE scores were significantly associated with worse respiratory mechanics (plateau and driving pressure) and gas exchange metrics (PaO2/FiO2 and ventilatory ratio), as well as higher plasma levels of IL-6, sRAGE and TNFR1 levels (p<0.05). RALE scores were independently associated with 90-day survival in a multivariate Cox proportional hazards model (adjusted hazard ratio 1.04[1.02-1.07], p=0.002). We validated significant associations of RALE scores with baseline severity and mortality in an independent dataset of 415 COVID-19 inpatients. CONCLUSION: Reproducible assessment of radiographic severity revealed significant associations with clinical and physiologic severity, host-response biomarkers and clinical outcome in COVID-19 pneumonia. Incorporation of radiographic severity assessments may provide prognostic and treatment allocation guidance in patients hospitalized with COVID-19.

Chest Radiograph Severity and Its Association With Outcomes in Subjects With COVID-19 Presenting to the Emergency Department.

BACKGROUND: Severity of radiographic abnormalities on chest radiograph in subjects with COVID-19 has been shown to be associated with worse outcomes, but studies are limited by different scoring systems, sample size, subject age, and study duration. Data regarding the longitudinal evolution of radiographic abnormalities and its association with outcomes are scarce. We sought to evaluate these questions using a well-validated scoring system (the Radiographic Assessment of Lung Edema [RALE] score) using data over 6 months from a large, multihospital health care system. METHODS: We collected clinical and demographic data and quantified radiographic edema on chest radiograph obtained in the emergency department (ED) as well as on days 1-2 and 3-5 (in those admitted) in subjects with a nasopharyngeal swab positive for SARS-CoV-2 by polymerase chain reaction (PCR) visiting the ED for coronavirus disease 2019 (COVID)-19-related complaints between March-September 2020. We examined the association of baseline and longitudinal evolution of radiographic edema with severity of hypoxemia and clinical outcomes. RESULTS: Eight hundred and seventy subjects were included (median age 53.6; 50.8% female). Inter-rate agreement for RALE scores was excellent (interclass correlation coefficient 0.84 [95% CI 0.82-0.87], P < .001). RALE scores correlated with hypoxemia as quantified by SpO2 /FIO2 (r = -0.42, P < .001). Admitted subjects had higher RALE scores than those discharged (6 [2-11] vs 0 [0-3], P < .001). An increase of RALE score ≥ 4 was associated with worse 30-d survival (P = .006). Larger increases in the RALE score were associated with worse survival. CONCLUSIONS: The RALE score was reproducible and easily implementable in adult subjects presenting to the ED with COVID-19. Its association with physiologic parameters and outcomes at baseline and longitudinally makes it a readily available tool for prognostication and early ICU triage, particularly in patients with worsening radiographic edema.

Plasma 1,3-ß-d-glucan levels predict adverse clinical outcomes in critical illness.

BACKGROUNDThe fungal cell wall constituent 1,3-ß-d-glucan (BDG) is a pathogen-associated molecular pattern that can stimulate innate immunity. We hypothesized that BDG from colonizing fungi in critically ill patients may translocate into the systemic circulation and be associated with host inflammation and outcomes.METHODSWe enrolled 453 mechanically ventilated patients with acute respiratory failure (ARF) without invasive fungal infection and measured BDG, innate immunity, and epithelial permeability biomarkers in serially collected plasma samples.RESULTSCompared with healthy controls, patients with ARF had significantly higher BDG levels (median [IQR], 26 pg/mL [15-49 pg/mL], P < 0.001), whereas patients with ARF with high BDG levels (≥40 pg/mL, 31%) had higher odds for assignment to the prognostically adverse hyperinflammatory subphenotype (OR [CI], 2.88 [1.83-4.54], P < 0.001). Baseline BDG levels were predictive of fewer ventilator-free days and worse 30-day survival (adjusted P < 0.05). Integrative analyses of fungal colonization and epithelial barrier disruption suggested that BDG may translocate from either the lung or gut compartment. We validated the associations between plasma BDG and host inflammatory responses in 97 hospitalized patients with COVID-19.CONCLUSIONBDG measurements offered prognostic information in critically ill patients without fungal infections. Further research in the mechanisms of translocation and innate immunity recognition and stimulation may offer new therapeutic opportunities in critical illness.FUNDINGUniversity of Pittsburgh Clinical and Translational Science Institute, COVID-19 Pilot Award and NIH grants (K23 HL139987, U01 HL098962, P01 HL114453, R01 HL097376, K24 HL123342, U01 HL137159, R01 LM012087, K08HK144820, F32 HL142172, K23 GM122069).

Circulating microbial cell-free DNA is associated with inflammatory host-responses in severe pneumonia.

Host inflammatory responses predict worse outcome in severe pneumonia, yet little is known about what drives dysregulated inflammation. We performed metagenomic sequencing of microbial cell-free DNA (mcfDNA) in 83 mechanically ventilated patients (26 culture-positive, 41 culture-negative pneumonia, 16 uninfected controls). Culture-positive patients had higher levels of mcfDNA than those with culture-negative pneumonia and uninfected controls (p<0.005). Plasma levels of inflammatory biomarkers (fractalkine, procalcitonin, pentraxin-3 and suppression of tumorigenicity-2) were independently associated with mcfDNA levels (adjusted p<0.05) among all patients with pneumonia. Such host-microbe interactions in the systemic circulation of patients with severe pneumonia warrant further large-scale clinical and mechanistic investigations.

The evolution of radiographic edema in ARDS and its association with clinical outcomes: A prospective cohort study in adult patients.

PURPOSE: To assess the longitudinal evolution of radiographic edema using chest X-rays (CXR) in patients with Acute Respiratory Distress Syndrome (ARDS) and to examine its association with prognostic biomarkers, ARDS subphenotypes and outcomes. MATERIALS AND METHODS: We quantified radiographic edema on CXRs from patients with ARDS or cardiogenic pulmonary edema (controls) using the Radiographic Assessment of Lung Edema (RALE) score on day of intubation and up to 10 days after. We measured baseline plasma biomarkers and recorded clinical variables. RESULTS: The RALE score had good inter-rater agreement (r = 0.83, p < 0.0001) applied on 488 CXRs from 129 patients, with higher RALE scores in patients with ARDS (n = 108) compared to controls (n = 21, p = 0.01). Baseline RALE scores were positively correlated with levels of the receptor for end-glycation end products (RAGE) in ARDS patients (p < 0.05). Baseline RALE scores were not predictive of 30- or 90-day survival. Persistently elevated RALE scores were associated with prolonged need for mechanical ventilation (p = 0.002). CONCLUSIONS: The RALE score is easily implementable with high inter-rater reliability. Longitudinal RALE scoring appears to be a reproducible approach to track the evolution of radiographic edema in patients with ARDS and can potentially predict prolonged need for mechanical ventilation.