Prevalence of phenotypes of acute respiratory distress syndrome in critically ill patients with COVID-19: a prospective observational study

Abstract

Background: In acute respiratory distress syndrome (ARDS) unrelated to COVID-19, two phenotypes, based on the severity of systemic inflammation (hyperinflammatory and hypoinflammatory), have been described. The hyperinflammatory phenotype is known to be associated with increased multiorgan failure and mortality. In this study, we aimed to identify these phenotypes in COVID-19-related ARDS.

Methods: In this prospective observational study done at two UK intensive care units, we recruited patients with ARDS due to COVID-19. Demographic, clinical, and laboratory data were collected at baseline. Plasma samples were analysed for interleukin-6 (IL-6) and soluble tumour necrosis factor receptor superfamily member 1A (TNFR1) using a novel point-of-care assay. A parsimonious regression classifier model was used to calculate the probability for the hyperinflammatory phenotype in COVID-19 using IL-6, soluble TNFR1, and bicarbonate levels. Data from this cohort was compared with patients with ARDS due to causes other than COVID-19 recruited to a previous UK multicentre, randomised controlled trial of simvastatin (HARP-2).

Findings: Between March 17 and April 25, 2020, 39 patients were recruited to the study. Median ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air (PaO₂/FiO₂) was 18 kpa (IQR 15-21) and acute physiology and chronic health evaluation II score was 12 (10-16). 17 (44%) of 39 patients had died by day 28 of the study. Compared with survivors, patients who died were older and had lower PaO₂/FiO₂. The median probability for the hyperinflammatory phenotype was 0·03 (IQR 0·01-0·2). Depending on the probability cutoff used to assign class, the prevalence of the hyperinflammatory phenotype was between four (10%) and eight (21%) of 39, which is lower than the proportion of patients with the hyperinflammatory phenotype in HARP-2 (186 [35%] of 539). Using the Youden index cutoff (0·274) to classify phenotype, five (63%) of eight patients with the hyperinflammatory phenotype and 12 (39%) of 31 with the hypoinflammatory phenotype died. Compared with matched patients recruited to HARP-2, levels of IL-6 were similar in our cohort, whereas soluble TNFR1 was significantly lower in patients with COVID-19-associated ARDS.

Interpretation: In this exploratory analysis of 39 patients, ARDS due to COVID-19 was not associated with higher systemic inflammation and was associated with a lower prevalence of the hyperinflammatory phenotype than that observed in historical ARDS data. This finding suggests that the excess mortality observed in COVID-19-related ARDS is unlikely to be due to the upregulation of inflammatory pathways described by the parsimonious model.

Funding: US National Institutes of Health, Innovate UK, and Randox.

Figure 1

Correlation matrix of the biomarkers measured at baseline in our cohort Increased size of the circles shows stronger correlation. Coefficients are derived using the Spearman's rank correlation coefficient. IL-6=interleukin 6. LDH=lactate dehydrogenase. TNFR1=tumour necrosis factor receptor superfamily member 1A.

Figure 2

Comparison of measures of creatinine, lactate dehydrogenase, and lymphocytes in the hyperinflammatory and hypoinflammatory phenotypes of COVID-19-associated ARDS Comparisons of creatinine (A), lactate dehydrogenase (B), and lymphocytes (C) between the hyperinflammatory and hypoinflammatory subgroups of the COVID-19 subset of the PHIND cohort. Phenotypes were assigned using the Youden index as the cutoff (≥0·274). Boxes show medians and IQRs; whiskers show the full range; and dots show individual observations. p values were calculated by Wilcoxon signed-rank test. ARDS=acute respiratory distress syndrome. PHIND=clinical evaluation of a point of care assay to identify PHenotypes IN the acute respiratory Distress syndrome.

Figure 3

Comparison of patient characteristics in the COVID-19-related ARDS cohort and the HARP-2 matched cohort Comparisons of APACHE II score (A) and measures of soluble TNFR1 (B), IL-6 (C), creatinine (D), and platelets (E) between the COVID-19 subset of the PHIND cohort and HARP-2 matched cohort. Boxes show medians and IQRs; whiskers show the full range; and dots show individual observations. p values were calculated by Wilcoxon signed-rank test. APACHE II=acute physiology and chronic health evaluation II. ARDS=acute respiratory distress syndrome. IL-6=interleukin 6. HARP-2=Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction. PHIND=clinical evaluation of a point of care assay to identify PHenotypes IN the acute respiratory Distress syndrome. TNFR1=tumour necrosis factor receptor superfamily member 1A.