Novel subtypes of severe COVID-19 respiratory failure based on biological heterogeneity: a secondary analysis of a randomized controlled trial

Abstract

Background: Despite evidence associating inflammatory biomarkers with worse outcomes in hospitalized adults with COVID-19, trials of immunomodulatory therapies have met with mixed results, likely due in part to biological heterogeneity of participants. Latent class analysis (LCA) of clinical and protein biomarker data has identified two subtypes of non-COVID acute respiratory distress syndrome (ARDS) with different clinical outcomes and treatment responses. We studied biological heterogeneity and clinical outcomes in a multi-institutional platform randomized controlled trial of adults with severe COVID-19 hypoxemic respiratory failure (I-SPY COVID).

Methods: Clinical and plasma protein biomarker data were analyzed from 400 trial participants enrolled from September 2020 until October 2021 with severe COVID-19 requiring ≥ 6 L/min supplemental oxygen. Seventeen hypothesis-directed protein biomarkers were measured at enrollment using multiplex Luminex panels or single analyte enzyme linked immunoassay methods (ELISA). Biomarkers and clinical variables were used to test for latent subtypes and longitudinal biomarker changes by subtype were explored. A validated parsimonious model using interleukin-8, bicarbonate, and protein C was used for comparison with non-COVID hyper- and hypo-inflammatory ARDS subtypes.

Results: Average participant age was 60 ± 14 years; 67% were male, and 28-day mortality was 25%. At trial enrollment, 85% of participants required high flow oxygen or non-invasive ventilation, and 97% were receiving dexamethasone. Several biomarkers of inflammation (IL-6, IL-8, IL-10, sTNFR-1, TREM-1), epithelial injury (sRAGE), and endothelial injury (Ang-1, thrombomodulin) were associated with 28- and 60-day mortality. Two latent subtypes were identified. Subtype 2 (27% of participants) was characterized by persistent derangements in biomarkers of inflammation, endothelial and epithelial injury, and disordered coagulation and had twice the mortality rate compared with Subtype 1. Only one person was classified as hyper-inflammatory using the previously validated non-COVID ARDS model.

Conclusions: We discovered evidence of two novel biological subtypes of severe COVID-19 with significantly different clinical outcomes. These subtypes differed from previously established hyper- and hypo-inflammatory non-COVID subtypes of ARDS. Biological heterogeneity may explain inconsistent findings from trials of hospitalized patients with COVID-19 and guide treatment approaches.

Keywords: Biological heterogeneity; COVID-19; Hypoxemic respiratory failure; Latent class analysis; Phenotyping; Protein biomarkers.

Fig. 1

Differences in the standardized values of each continuous variable by subtype assignment. The variables are sorted based on the degree of separation between the two subtypes. A standardized value of + 1 signifies that the mean value for a given subtype was one standard deviation higher than the mean value in the cohort as a whole. Ang = angiopoietin; BMI = body mass index; BNP = brain natriuretic peptide; CRP = C reactive protein; ICAM1 = intercellular adhesion molecule-1; IL = interleukin; IP10 = interferon-gamma inducible protein of 10 kDa; MMP8 = matrix metalloproteinase-8; NLR = neutrophil to lymphocyte ratio; PAI1 = plasminogen activator inhibitor-1; PTT = partial thromboplastin time; RAGE = soluble receptor for advanced glycation end products; SPD = surfactant protein D; TNFR1 = tumor necrosis factor receptor-1; VEGF = vascular endothelial growth factors; WBC = white blood cell count

Fig. 2

Clinical outcomes by latent class analysis (LCA) subtype assignment. A Mortality rates by subtype assignment stratified by WHO ordinal scale for COVID-19 severity upon trial enrollment; Within strata comparisons done using Chi-squared test or Fisher’s exact test where appropriate and p-value < 0.05 is depicted via Asterix. B Survival and recovery for Subtype 2 compared with Subtype 1 stratified by WHO ordinal scale for COVID-19 severity upon trial enrollment; For time to death, estimates are derived from Fine-Gray subdistribution hazard model with recovery as the competing event; For time to recovery, estimates are derived from Fine-Gray subdistribution hazard model with death as the competing event. ***P value < 0.001. WHO 5: hospitalized, noninvasive mechanical ventilation or high-flow nasal cannula (HFNC); WHO 6: hospitalized, intubation and invasive mechanical ventilation (IMV); WHO 7: hospitalized, IMV + additional support such as pressors or extracardiac membranous oxygenation

Fig. 3

Change in log10 biomarker concentration over time by subtype assignment in the control arm (N = 142). A Biomarkers of inflammation, B endothelial injury, C alveolar epithelial injury, and D disordered coagulation. Y-axis is the log10 concentration of biomarker. Estimates with 95% confidence intervals derived from linear mixed effects models. Asterisks denote significant difference in the slope of biomarker change over time between Subtype 1 and Subtype 2 based on Chi-squared test of interaction. *p value < 0.05. **p value < 0.005. ***p value < 0.001