Systemic role of orexin A, substance P, bradykinin, and DABK in severe COVID-19 and 2.5-yr follow-ups: an observational study

Background: Orexin A regulates sleep–wake cycles, arousal, and energy homeostasis, linking it to the renin–angiotensin system and substance P. Dysfunction in these pathways occurs in acute and long-term COVID-19, including post-COVID syndrome. Methods: This observational study analysed plasma orexin A, substance P, bradykinin, and des-Arg⁹-bradykinin (DABK) in 78 ICU COVID-19 patients, 14 survivors of severe COVID-19 (2.5-yr follow-ups), and 14 healthy controls. Results: During acute COVID-19, bradykinin and substance P were significantly reduced, whereas DABK was elevated compared with healthy controls and 2.5-yr follow-ups. Orexin A concentration correlated with ICU survival (Cohen's d=0.4), length of stay (LOS; r=–0.26, P=0.02), and sedation concentrations. Intriguingly, substance P plasma concentrations were elevated in 2.5-yr follow-ups. Plasma orexin A, substance P, and bradykinin increased with lower Richmond Agitation–Sedation Score (RASS): a combination of orexin A, substance P, and bradykinin concentrations at RASS –3 to –5 distinguished survivors from non-survivors of COVID-19 when categorised by age. Conclusions: Changes in the bradykinin axis, affecting substance P and orexin A signalling, are associated with severe COVID-19, ICU LOS, and survival. Elevated substance P concentrations in the 2.5-yr follow-up cohort may be associated with physical, cognitive, and neuropsychological impairments commonly seen in post-ICU syndrome and post-COVID syndrome. The predictive values of orexin A, substance P, bradykinin, and DABK and the complex interplay between the renin–angiotensin system and the orexinergic system in severe, critical illnesses or viral diseases will be investigated in future studies.