Leukotriene modifying drugs in COVID-19 treatment
Due to the involvement of complement, coagulation and inflammation in COVID-19,32,93,94 anti-inflammatory drugs have gained great interest as disease modifiers (Fig. 3) .95 Already at the beginning of the COVID-19 pandemic, researchers suggested the use of the LTRA montelukast for treatment of COVID-19.96-98 The reason for this early interest in LT modifying drugs was on the one hand related to the viral cell entry via ACE2 receptors and the known inhibitory effect of montelukast on bradykinin-related airway response99and, on the other hand to the fact that patients with severe COVID-19 develop an overwhelming state of inflammation that has been labelled COVID-19 cytokine storm syndrome (CSS).32,100,101Moreover, the most important cause of death in COVID-19 was recognized as the progressive respiratory failure with limited response to treatment together with hyperinflammation and hypoxia, quite similar to a severe Acute Respiratory Distress Syndrome (ARDS), which has been demonstrated to be characterized by an elevated level of LTs.102 Of note, high levels of LTE4have been detected in bronchoalveolar lavage (BAL) of hospitalized patients with severe COVID-19,34 as well as there is a shift in serum eicosanoids into the increase of 5-LOX products in such patients.35 Indeed, specific benefits of montelukast, or other LTRAs, have been suggested in the situation of hyperinflammation and massive cytokine release103 to reduce elevated levels of LPS-induced IL-6, TNF-α, and MCP-1 production in the peripheral blood MNCs of patients with asthma,104 as well as to reduce levels of many cytokines and chemokines (IL-4, IL-5, IL-1β, TNF-α, RANTES, and IL-8) in nasal mucosa105 possibly due to modulation of TNF-α-stimulated IL-8 expression through changes in NF-κB p65-associated histone acetyltransferase activity.50 In addition to its anti-inflammatory properties in humans, in silico studies also suggested, but still to be demonstrated, a direct anti-viral effect by showing a high affinity binding of montelukast to the terminal end of the virus’ main protease enzyme needed for viral protein assembly.106
Thus, with increasing understanding of disease mechanisms, LTRAs have been also considered for treatment of COVID-19. Indeed, in a small retrospective study on COVID-19 hospitalized subjects, patients receiving montelukast had fewer episodes of confirmed COVID-19 or experienced significantly fewer events of clinical deterioration compared to patients not receiving montelukast.107,108These lipid mediators might not only contribute to inflammation and lung pathologies associated with COVID-19, but can also be involved in thrombosis, fibrosis, neuronal damage and cardiovascular disease.97,109,110 Accordingly, since May 2020 a series of clinical trials involving montelukast have been registered (https://clinicaltrials.gov). However, not only antagonism of the CysLT receptors could be beneficial for patients with COVID-19, but interventions targeting LT biosynthesis, using eg. Zileuton, might represent promising targets, specifically at the turning point from a mild to critical disease course.111