key: cord-0728479-vvvuum69
authors: Kapandji, Natacha; Yvin, Elise; Devriese, Magali; de Margerie-Mellon, Constance; Moratelli, Giulia; Lemiale, Virginie; Jabaudon, Matthieu; Azoulay, Elie; Constantin, Jean-Michel; Dumas, Guillaume
title: Importance of Lung Epithelial Injury in COVID-19–associated Acute Respiratory Distress Syndrome: Value of Plasma Soluble Receptor for Advanced Glycation End-Products
date: 2021-03-30
journal: American journal of respiratory and critical care medicine
DOI: 10.1164/rccm.202104-1070le
sha: b74d29ced9fc81087ad47259e41aff3e89f383af
doc_id: 728479
cord_uid: vvvuum69

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Levels of plasma sRAGE were measured in duplicate from thawed samples collected within 24 hours after MV initiation. A commercially available sandwich enzyme immunoassay kit (Human sRAGE Quantikine ELISA Kit; R&D Systems) was used following recommendations from the manufacturer.

Patients with CARDS were then compared with a historical multicentric prospective cohort of patients with ARDS in whom plasma sRAGE had been measured (7) and with control patients (e.g., mechanically ventilated patients without COVID-19 infection or ARDS, n = 15).

Continuous variables are described as medians (interquartile ranges) and compared using the Wilcoxon's rank sum test or the Kruskal-Wallis test; categorical variables are summarized by counts (percentages) and compared using the Fisher exact test. Correlations were assessed with the Rho Spearman's correlation test. Prognosis value of sRAGE on Day-90 mortality was assessed using Cox model adjusted on potential confounders (e.g., ARDS etiology, cardiovascular risk factors, body mass index, driving pressure, and Pa O 2 /FI O 2 ).

All tests were two-sided and P values ,5% were considered to indicate significant associations. Analyses were performed using R statistical platform, version 3.0.2.

Characteristics of patients with COVID-19 ARDS. Overall, 50 patients with CARDS (median [interquartile range], 62.0 [54.0-68.7] yr of age; 68% male) were included. Median time from symptoms onset to invasive MV initiation was 9.0 (7.0-14.0) days. For further details, see Table 1 .

Baseline plasma sRAGE correlates with lung injury severity and outcome in COVID-19. At baseline, plasma sRAGE was 4,044.0 (1,763.0-4,768.0) pg/ml and significantly differed from control (525.0 [411.0-638.5] pg/ml; P , 0.001; Figure 1 ).

Baseline plasma sRAGE correlated with Pa O 2 /FI O 2 (Spearman's r = 20.49; P = 0.001), ventilatory ratio (r = 0.36; P = 0.019), shunt (r = 0.39; P = 0.01), and RALE score (median score, 28 [18-36]; r = 0.64; P , 0.01).

The recruitment-to-inflation ratio was measured in 16 patients (32%) and high potential for recruitability was observed in 6 (37.5%). Plasma sRAGE levels were higher in patients with high potential for recruitability (4, 245 Figure 1 ). Overall, Day-90 mortality rate was 54% in CARDS and 36% in non-COVID-19 ARDS (P = 0.045). Adjusted on potential confounders, baseline plasma sRAGE levels were significantly associated with mortality (adjusted hazard ratio, 1.51 [1.05-2.16] per one log increment; P = 0.02).

Whether CARDS-related lung injury is similar to that from other causes of ARDS is an important question. The answer may guide the ventilatory strategy and carry some prognostic information. Using a well-characterized marker of lung epithelial injury, this study suggests that CARDS includes a component of pulmonary alveolar damage higher than other causes of ARDS. Moreover, as in non-COVID-19 ARDS, plasma sRAGE is associated with CARDS severity and outcome, especially lung edema, assessed by baseline RALE score and oxygenation impairment.

Since the onset of the pandemic, CARDS has been suggested to be an atypical subset of ARDS (2, 8) . This assertion has been recently challenged, mainly through comparisons of lung mechanics parameters (9) . Although sRAGE production could have several sources, numerous works have provided evidence that alveolar type I cells are the main source of plasma sRAGE, and that sRAGE is a reliable marker of diffuse lung alveolar injury and impaired fluid clearance in both clinical and experimental models of ARDS (3) . In this study, we found a marked elevation in sRAGE levels among patients with CARDS, which argues for intense lung epithelial injury. This is consistent with recent pathological reports from postmortem lung biopsies, in which diffuse alveolar damage was the most common histological finding (10).

This study has some limitations. First, the limited number of patients from a single center requires additional data to confirm this hypothesis. Second, plasma sRAGE was only measured at baseline and the value of changes over time is unknown.

In summary, our findings suggest that lung epithelial injury, as reflected by plasma sRAGE, may be a key pathophysiological feature with prognostic information in CARDS.

Author disclosures are available with the text of this letter at www.atsjournals.org. 

To the Editor:

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide (1) . Most of the poor outcomes of COPD occur during acute exacerbations (AECOPD) (2) , which are frequently triggered by a respiratory tract infection (3) . IgG deficiency has long been identified as a cause of recurrent respiratory tract infections and is thought to be a risk factor for developing chronic respiratory diseases such as idiopathic bronchiectasis (4) . Recently, we showed that serum IgG deficiency is a significant risk factor for AECOPD and related hospitalizations (1) . Here, we examined the relationship between serum IgG levels and 1-year mortality in patients with COPD. Some of the results of this study have been previously reported in an abstract (5) .

All patients provided written informed consent. (3) . Briefly, the Rapid Transition Program included patients hospitalized with AECOPD (n = 489) and clinically stable patients, who were recruited from a COPD clinic in the same hospital (n = 132). None had significant bronchiectasis either by history or by thoracic computed tomography scan. Samples were collected and were processed per standardized protocol and stored at 280 C. Serum IgG levels were measured via liquid chromatography-tandem mass spectrometry as previously described (6) . IgG measurements were processed in the clinical laboratory at St. Paul's Hospital, Vancouver, British Columbia, Canada. After enrollment, patients were followed for 1 year, during which their vital status was ascertained through hospital records, which were validated by death certificates. Cox regression modeling, which adjusted Author Contributions: N.M.A. had full access to all the data in the study, takes responsibility for the integrity of the data and the accuracy of the data analysis, and contributed to drafting the manuscript. D.D.S. contributed substantially to the study design, data analysis, and interpretation and had authority over manuscript preparation and the decision to submit the manuscript for publication. All authors contributed to the critical revision of the manuscript for important intellectual content and gave final approval of the version to be published.

Originally Published in Press as DOI: 10.1164/rccm.202102-0382LE on May 4, 2021

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