RESUMO
Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete understanding of potentially druggable immune mediators of disease. To advance this, we present a comprehensive multi-omic blood atlas in patients with varying COVID-19 severity and compare with influenza, sepsis and healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity revealed cells, their inflammatory mediators and networks as potential therapeutic targets, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Tensor and matrix decomposition of the overall dataset revealed feature groupings linked with disease severity and specificity. Our systems-based integrative approach and blood atlas will inform future drug development, clinical trial design and personalised medicine approaches for COVID-19.
Assuntos
COVID-19 , SepseRESUMO
Coronavirus disease 2019 (COVID-19) mortality is associated with hypoxaemia, multiorgan failure, and thromboinflammation. However severity of disease varies considerably and understanding physiological changes that may link to poor outcomes is important. Although increased serum ferritin has been observed in COVID-19 patients consistent with inflammation, other iron parameters have not been examined to our knowledge. Because iron is required for immunity and oxygen utilisation, and dysregulated iron homeostasis has been observed in COPD, we investigated serum iron concentrations in 30 patients with COVID-19 requiring ICU admission. All patients had low serum iron but patients with severe hypoxemic respiratory failure had more profound hypoferraemia. The area under the curve for receiver operating characteristic curves for serum iron to identify severe hypoxemia was 0.95; the optimal Youden Index for distinguishing between severe and non-severe hypoxemia was a serum iron concentration of 2.9 micromol/L. By linear regression, serum iron was associated with lymphocyte count and PaO2/FiO2. In conclusion, profound hypoferraemia identifies COVID-19 patients with severe hypoxaemia. Serum iron is a simple biomarker that could be usefully employed to stratify patients and monitor disease. Severe hypoferraemia may plausibly impair critical iron-dependent processes such as lymphocyte responses and hypoxia sensing, contributing to pathology, and is potentially treatable.