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