ABSTRACT
Initially, it had been assumed that in cases of SARS-CoV-2 infection comorbidity with psychiatric disorders worsens clinical outcomes. This was attributed to patients' poor overall health conditions, concomitant illnesses and unhealthy lifestyles. However, only schizophrenia is in a statistically significant correlation with very serious conditions leading to death, possibly as a result of underlying immune dysfunctions. Clozapine (an antipsychotic used in therapy of treatment resistant schizophrenia) seems to decrease the likelihood of recovery in COVID-19 patients, however admi nistration of antidepressant medications appears to increase it. It has also been justified that among these antidepressant drugs, fluvoxamin shows to have an effect in inhibiting cytokine storms and reducing the severity of the COVID-19 infection. Most recent data suggest that the well-known antiviral effect of lithium is also present in patients with COVID-19 infection.
ABSTRACT
PURPOSE: We aimed to critically review the available information on the potential contribution of excessive kallikrein-kinin systems (KKSs) activation to severe respiratory inflammation in SARS-CoV-2 infection, and the likely consequence of ACE inhibition in seriously affected patients. METHODS: The literature related to the above topic was reviewed including papers that analysed the connections, actions, interactions, consequences and occasionally suggestions for rational interventions. RESULTS/CONCLUSION: Severe broncho-alveolar inflammation seems to be caused, at least in part, by upregulation of the KKS that increases plasma and/or local tissue concentrations of bradykinin (BK) in patients with COVID-19 infection. Besides KKS activation, suppression of ACE activity results in decreased bradykinin degradation, and these changes in concert can lead to excessive BK B1 and B2 receptor (BKB1R/BKB2R) activation. Aminopeptidase P (APP), and carboxypeptidase N also degrade bradykinin, but their protein expression and activity are unclear in COVID-19 infection. On the other hand, ACE2 expression is upregulated in patients with COVID-19 infection, so ACE2 activity is unlikely to be decreased despite blockade of part of ACE2 by the virus for entry into the cells. ACE2 cleaves lys-des-arginine9BK and arg-des-arginine9BK, the active metabolites of bradykinin, which stimulate the BKB1R receptor. Stimulation of BKB1R/BKB2R can exacerbate the pulmonary inflammatory response by causing vascular leakage and edema, vasodilation, smooth muscle spasm and stimulation of pain afferent nerves. Despite all uncertainties, it seems rational to treat comorbid COVID patients with serious respiratory distress syndrome with ARBs instead of high-dose ACE inhibitor (ACEi) that will further decrease bradykinin degradation and enhance BKB1R/BKB2R activation, but ACEi may not be contraindicated in patients with mild pulmonary symptoms.