A Novel Strategy to Mitigate the Hyperinflammatory Response to COVID-19 by Targeting Leukotrienes

Abstract

SARS-CoV-2 causing coronavirus disease 2019 (COVID-19) has wreaked havoc during the global pandemic of 2020 infecting millions and leaving over a half million dead. As a new virus, not previously in the human population, but with similarities to other coronaviruses causing severe acute respiratory distress syndrome (SARS/ARDS), and no known treatments, the race to re-purpose existing drugs and to enlist novel therapeutics is underway. In the half-year since the first cases, we have acquired substantial knowledge of this virus and the clinical course of COVID-19 progression. Results from early clinical trials have revealed two treatments (remdesivir, dexamethasone) that mitigate disease progression but clearly, there is much room for improvement. Initial case reports indicated many succumb to COVID-19 of hypoxic respiratory failure due to ARDS. However, ensuing studies revealed an atypical, immune cell-sequestered, vasculature-inflamed state leading to multiorgan thrombotic complications and end organ failure likely due to hyperinflammatory host responses. This Perspective focuses on a potential mechanism for a key COVID-19 disease progression turning point related to vascular and airway inflammation. The leukotriene lipid mediators have been overlooked with discussion centering on cytokine storms unleashing the deadly form of COVID-19. Leukotrienes possess some of the most potent known activities on immune cell trafficking and vascular leakage. We offer a simple treatment paradigm using two generic drugs targeting the hyperinflammatory response that characterizes the turning point from mild to severe/critical COVID-19 by targeting leukotriene biosynthesis with zileuton (Zyflo^® controlled release formulation) and antagonism of the cysteinyl leukotriene 1 receptor with montelukast (Singulair^®).

Keywords: COVID-19; SARS-CoV-2; clinical trial; coronavirus; cytokine storm; inflammatory response; leukotrienes; vascular leak.

Figure 1

Schematic depictions of mild, moderate, severe, and critical cases of coronavirus disease 2019 (COVID-19) including some symptoms, laboratory findings, and clinical timeline. The disease course is highly variable with dotted lines representing this unpredictability. Criteria are based on World Health Organization categories. In a large cohort of COVID-19 patients that experience symptoms (mentioned in Berlin et al., 2020), percentages are shown in three categories mild, severe and critical. Moderate were not included (shown by *). Up to half of critical cases may die from COVID-19 complications with fewer deaths in the severe category. Lab data are based on (England et al., 2020; table 6) and are meant to show approximations for each marker. Units for CRP, D-dimer, Ferritin, IL-6 are mg/L, μg/ml, μg/L, and pg/ml, respectively. The numbers in the LTE₄ column, at this point, are hypothetical and based on baseline data of urinary LTE₄ levels of ≈1 ng/mg creatinine in normal controls and 4 ng/mg creatinine in severe ARDS patients (Bernard et al., 1991). These values would need to be validated in SARS-CoV-2 infected individuals. LTE₄ is the major urinary metabolite of the cysteinyl leukotrienes LTC₄ and LTD₄.

Figure 2

Vascular leakage, inflammation-provoking, and thrombotic events in coronavirus disease 2019 (COVID-19). A normal alveolus in the healthy state with associated capillary vessel (top) and SARS-CoV-2 infected alveolus with surrounding vasculature (middle) are shown. Potential roles for LTB₄ to promote inflammatory cell influx into the airways and for CysLTs to initiate vascular leakage are depicted. LTB₄ and CysLTs can be synthesized de novo by alveolar macrophages, infiltrating leukocytes, sentinel mucosal mast cells (not shown here) and via interactions of inflammatory cells with endothelial cells. The figures are “cartoon” representations, so cells/viruses/blood vessels are not to scale. Concepts of the model indicating that COVID-19 is an endothelial disorder are based on (Ackermann et al., 2020; Becker, 2020; Sardu et al., 2020; Teuwen et al., 2020; Varga et al., 2020) but with an emphasis here on leukotriene inflammatory mediators. Depiction of leukotriene biosynthesis along with the two drugs zileuton and montelukast proposed to mitigate disease progression of COVID-19 (bottom). Zileuton, acting intracellularly, inhibits 5-lipoxygenase (5-LO) to decrease leukotriene ligands able to bind downstream receptors BLT₁ (mediating neutrophil/T lymphocyte trafficking) and CysLT receptors (promoting vascular leakage). Montelukast, acting extracellularly, antagonizes selectively CysLT₁ to dampen inflammation and reduce vascular leakage. FLAP, 5-lipoxygenase-activating protein.