Impaired Kallikrein-Kinin System in COVID-19 Patients' Severity.

COVID-19 has emerged as a devastating disease in the last 2 years. Many authors appointed to the importance of kallikrein-kinin system (KKS) in COVID-19 pathophysiology as it is involved in inflammation, vascular homeostasis, and coagulation. We aim to study the bradykinin cascade and its involvement in severity of patients with COVID-19. This is an observational cohort study involving 63 consecutive patients with severe COVID-19 pneumonia and 27 healthy subjects as control group. Clinical laboratory findings and plasma protein concentration of KKS peptides [bradykinin (BK), BK1-8], KKS proteins [high-molecular weight kininogen (HK)], and KKS enzymes [carboxypeptidase N subunit 1 (CPN1), kallikrein B1 (KLKB1), angiotensin converting enzyme 2 (ACE2), and C1 esterase inhibitor (C1INH)] were analyzed. We detected dysregulated KKS in patients with COVID-19, characterized by an accumulation of BK1-8 in combination with decreased levels of BK. Accumulated BK1-8 was related to severity of patients with COVID-19. A multivariate logistic regression model retained BK1-8, BK, and D-dimer as independent predictor factors to intensive care unit (ICU) admission. A Youden's optimal cutoff value of -0.352 was found for the multivariate model score with an accuracy of 92.9%. Multivariate model score-high group presented an odds ratio for ICU admission of 260.0. BK1-8 was related to inflammation, coagulation, and lymphopenia. Our data suggest that BK1-8/BK plasma concentration in combination with D-dimer levels might be retained as independent predictors for ICU admission in patients with COVID-19. Moreover, we reported KKS dysregulation in patients with COVID-19, which was related to disease severity by means of inflammation, hypercoagulation, and lymphopenia.

Does eNOS derived nitric oxide protect the young from severe COVID-19 complications?

The COVID-19 pandemic poses an imminent threat to humanity, especially to the elderly. The molecular mechanisms underpinning the age-dependent disparity for disease progression is not clear. COVID-19 is both a respiratory and a vascular disease in severe patients. The damage endothelial system provides a good explanation for the various complications seen in COVID-19 patients. These observations lead us to suspect that endothelial cells are a barrier that must be breached before progression to severe disease. Endothelial intracellular defences are largely dependent of the activation of the interferon (IFN) system. Nevertheless, low type I and III IFNs are generally observed in COVID-19 patients suggesting that other intracellular viral defence systems are also activated to protect the young. Intriguingly, Nitric oxide (NO), which is the main intracellular antiviral defence, has been shown to inhibit a wide array of viruses, including SARS-CoV-1. Additionally, the increased risk of death with diseases that have underlying endothelial dysfunction suggest that endothelial NOS-derived nitric oxide could be the main defence mechanism. NO decreases dramatically in the elderly, the hyperglycaemic and the patients with low levels of vitamin D. However, eNOS derived NO occurs at low levels, unless it is during inflammation and co-stimulated by bradykinin. Regrettably, the bradykinin-induced vasodilation also progressively declines with age, thereby decreasing anti-viral NO production as well. Intriguingly, the inverse correlation between the percentage of WT eNOS haplotype and death per 100K population could potentially explain the disparity of COVID-19 mortality between Asian and non-Asian countries. These changes with age, low bradykinin and NO, may be the fundamental reasons that intracellular innate immunity declines with age leading to more severe COVID-19 complications.

Does hereditary angioedema make COVID-19 worse?

The coronavirus disease 2019 (COVID-19) pandemic has spread rapidly worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for COVID-19, enters host cells via angiotensin-converting enzyme 2 (ACE2) and depletes ACE2, which is necessary for bradykinin metabolism. The depletion of ACE2 results in the accumulation of des-Arg (9)-bradykinin and possible bradykinin, both of which bind to bradykinin receptors and induce vasodilation, lung injury, and inflammation. It is well known that an overactivated contact system and excessive production of bradykinin comprise the key mechanisms that drive the pathogenesis of hereditary angioedema (HAE). It is reasonable to speculate that COVID-19 may increase disease activity in patients with HAE and vice versa. In this review, we explore the potential interactions between COVID-19 and HAE in terms of the contact system, the complement system, cytokine release, increased T helper 17 cells, and hematologic abnormalities. We conclude with the hypothesis that comorbidity with HAE might favor COVID-19 progression and may worsen its outcomes, while COVID-19 might in turn aggravate pre-existing HAE and prompt the onset of HAE in asymptomatic carriers of HAE-related mutations. Based on the pathophysiologic links, we suggest that long-term prophylaxis should be considered in patients with HAE at risk of SARS-CoV-2 infection, especially the prophylactic use of C1 inhibitor and lanadelumab and that HAE patients must have medications for acute attacks of angioedema. Additionally, therapeutic strategies employed in HAE should be considered for the treatment of COVID-19, and clinical trials should be performed.