Background: Severe acute respiratory syndrome (SARS) and acute respiratory distress syndrome (ARDS) are often considered separate clinico-radiological entities. Whether these conditions also present a single process-specific systemic biomolecular phenotype and how this relates to patient outcomes remains unknown. A prospective cohort study was conducted, including adult patients admitted to the ICU and general floors for COVID-19-related (COVID+) or non-COVID-19-related (COVID−) acute respiratory failure during the main phase of the pandemic. The primary objective was to study blood biomarkers and outcomes among different groups and severity subsets. Results: A total of 132 patients were included, as follows: 67 COVID+, 54 COVID− (with 11 matched control subjects for biomarker reference), and 58 of these patients allowed for further pre- and post-analysis. The baseline apelin (APL) levels were higher in COVID+ patients (p < 0.0001 vs. COVID− patients) and in SARS COVID+ patients (p ≤ 0.02 vs. ARDS), while the IL-6 levels were higher in ARDS COVID− patients (p ≤ 0.0001 vs. SARS). Multivariable logistic regression analyses with cohort biomarkers and outcome parameters revealed the following: (i) log-transformed neprilysin (NEP) activity was significantly higher in COVID+ patients (1.11 [95% CI: 0.4–1.9] vs. 0.37 [95% CI: 0.1–0.8], fold change (FC): 1.43 [95% CI: 1.04–1.97], p = 0.029) and in SARS patients (FC: 1.65 [95% CI: 1.05–2.6], p = 0.032 vs. non-SARS COVID+ patients, and 1.73 [95% CI: 1.19–2.5], p = 0.005 vs. ARDS COVID− patients) and (ii) higher lysyl oxidase (LOX) activity and APL levels were respectively associated with death and a shorter length of hospital stay in SARS COVID+ patients (Odds Ratios (OR): 1.01 [1.00–1.02], p = 0.05, and OR: −0.007 [−0.013–0.0001], p = 0.048). Conclusion: Process-specific blood biomarkers exhibited distinct profiles between COVID+ and COVID− patients, and across stages of severity. NEP and LOX activities, as well as APL levels, are particularly linked to COVID+ patients and their outcomes (ClinicalTrials.gov Identifier: NCT04632732).
