Targeted plasma proteomics reveals signatures discriminating COVID-19 from sepsis with pneumonia

Abstract

Background COVID-19 remains a major public health challenge, requiring the development of tools to improve diagnosis and inform therapeutic decisions. As dysregulated inflammation and coagulation responses have been implicated in the pathophysiology of COVID-19 and sepsis, we studied their plasma proteome profiles to delineate similarities from specific features. Methods We measured 276 plasma proteins involved in Inflammation, organ damage, immune response and coagulation in healthy controls, COVID-19 patients during acute and convalescence phase, and sepsis patients; the latter included (i) community-acquired pneumonia (CAP) caused by Influenza, (ii) bacterial CAP, (iii) non-pneumonia sepsis, and (iv) septic shock patients. Results We identified a core response to infection consisting of 42 proteins altered in both COVID-19 and sepsis, although higher levels of cytokine storm-associated proteins were evident in sepsis. Furthermore, microbiologic etiology and clinical endotypes were linked to unique signatures. Finally, through machine learning, we identified biomarkers, such as TRIM21, PTN and CASP8, that accurately differentiated COVID-19 from CAP-sepsis with higher accuracy than standard clinical markers. Conclusions This study extends the understanding of host responses underlying sepsis and COVID-19, indicating varying disease mechanisms with unique signatures. These diagnostic and severity signatures are candidates for the development of personalized management of COVID-19 and sepsis.

A complement atlas identifies interleukin-6–dependent alternative pathway dysregulation as a key druggable feature of COVID-19

“…Further research into IL-6–dependent alternative pathway hyperactivation could be relevant in the context of other complement-dependent diseases, such as C3 glomerulopathy. In addition, complement blockade might also ameliorate other forms of lung injury and sepsis, given available preclinical and clinical evidence ( 67 , 75 ), and large increases in IL-6 in non–COVID-19 pneumonia and sepsis ( 76 ). Together, these results point to complement activation as a key druggable feature of COVID-19.…”

A Complement Atlas identifies interleukin 6 dependent alternative pathway dysregulation as a key druggable feature of COVID-19

“…Compared to C5 inhibition, anti-IL-6 has a much slower impact on complement activity though 34 , and combining these therapies might have synergistic effects. Complement blockade might also ameliorate other forms of lung injury and sepsis, given available (pre)clinical evidence 61, 69 and large increases of IL-6 in non- COVID-19 pneumonia and sepsis 70 . Taken together, these results point to complement activation as a key druggable feature of COVID-19.…”

A Reduced Proteomic Signature in Critically Ill Covid-19 Patients Determined With Plasma Antibody Micro-array and Machine Learning

“…While these studies identify a number of important biomarkers, they did not evaluate their effectiveness in a single combined model, which decreases the likelihood of crossidentity concerns with other diseases. The novel proteins identi ed in our study may be attributed to our use of an immune microarray platform, while other studies utilized mass spectrometry or proximity extension assays (174)(175)(176)(177)(178)(179). Pathway analysis was used in previous studies to help understand COVID-19 pathophysiology (176, 178, 179); however, our approach utilized NLP to identify organ and cell expression patterns.…”