Effects of non-steroidal anti-inflammatory drugs and other eicosanoid pathway modifiers on antiviral and allergic responses: EAACI task force on eicosanoids consensus report in times of COVID-19

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) and other eicosanoid pathway modifiers are among the most ubiquitously used medications in the general population. Their broad anti-inflammatory, antipyretic, and analgesic effects are applied against symptoms of respiratory infections, including SARS-CoV-2, as well as in other acute and chronic inflammatory diseases that often coexist with allergy and asthma. However, the current pandemic of COVID-19 also revealed the gaps in our understanding of their mechanism of action, selectivity, and interactions not only during viral infections and inflammation, but also in asthma exacerbations, uncontrolled allergic inflammation, and NSAIDs-exacerbated respiratory disease (NERD). In this context, the consensus report summarizes currently available knowledge, novel discoveries, and controversies regarding the use of NSAIDs in COVID-19, and the role of NSAIDs in asthma and viral asthma exacerbations. We also describe here novel mechanisms of action of leukotriene receptor antagonists (LTRAs), outline how to predict responses to LTRA therapy and discuss a potential role of LTRA therapy in COVID-19 treatment. Moreover, we discuss interactions of novel T2 biologicals and other eicosanoid pathway modifiers on the horizon, such as prostaglandin D2 antagonists and cannabinoids, with eicosanoid pathways, in context of viral infections and exacerbations of asthma and allergic diseases. Finally, we identify and summarize the major knowledge gaps and unmet needs in current eicosanoid research.

Keywords: COVID-19; LTRA; NSAID; asthma; biologicals.

FIGURE 1

Eicosanoid biosynthesis and signaling pathways are therapeutic targets of medications used in the treatment of infections, acute and chronic inflammatory diseases (including asthma and allergy) and pain. Glucocorticosteroids (GCs), non‐steroidal anti‐inflammatory drugs (NSAIDs), leukotriene receptor antagonists (LTRAs, e.g., montelukast, zafirlukast, pranlukast), 5‐lipoxygenase (5‐LOX) inhibitor, zileuton, as well as still clinically tested, timapiprant and setitpiprant act directly on the synthesis of eicosanoid mediators or their signaling molecules and receptors. Biosynthesis of endocannabinoids (2‐AG, AEA) interfere with eicosanoids metabolic pathways. 2‐AG—2‐Arachidonoyl‐glycerol (endocannabinoid); AEA—arachidonyl‐ethanolamide (endocannabinoid); COX—cyclooxygenase; Cyt—cytochrome; EET—epoxyeicosatrienoic acid; GC—glucocorticoids; HETE—hydroxyeicosatetraenoic acid; HPETE—hydroperoxyeicosatetraenoic acid; LOX—lipoxygenase; LTE₄—leukotriene; LTRA—leukotriene receptor antagonists; LX—lipoxin; PLA—phospholipase; PG—prostaglandin; and TX—thromboxane

FIGURE 2

Eicosanoid pathways in viral infections and allergic inflammation of the respiratory airways are affected by several groups of medications. Eicosanoids are important immune mediators coordinating the inflammatory response to viral infections and allergen challenges between bronchial epithelial cells, airway‐resident and airway‐infiltrating immune cells. Several groups of drugs used in the treatment of allergic diseases and respiratory tract infections interfere with eicosanoid production and signaling pathways. Glucocorticoids (GCs) reduce the activity of phospholipase A₂ (PLA₂) and COX‐2, therefore restricting both the upstream substrate for eicosanoid production and subsequent enzyme. NSAIDs block COX‐1‐ and COX‐2‐mediated synthesis of prostaglandins by both bronchial epithelial cells and immune cells. This reduces tissue inflammation and alleviates the symptoms of infection, but at the same time affects the antiviral response. LTRAs block eicosanoid leukotriene signaling at the receptor level, reducing activation of granulocytes. Biologicals used in the treatment of allergic diseases (anti‐IL‐5, anti‐IL‐5Rα, anti‐IL‐4Rα, and anti‐IgE) interfere with the eicosanoid signaling in a non‐direct manner, by preventing undue activation of eosinophils and Th2 cells, as well as degranulation of basophils and mast cells. BAS—basophil; COX‐1—cyclooxygenase 1; CysLTs—cysteinyl leukotrienes; DC—dendritic cell; EOS—eosinophil; GCs—glucocorticoids; IFN—interferon; IL—interleukin; LOX—lipoxygenase; LTE₄—leukotriene E4; LTRA—leukotriene receptor antagonists; LXA₄—lipoxin A4; MC—mast cell; MO—monocyte; Mθ—macrophage; NEU—neutrophil; NSAIDs—non‐steroidal anti‐inflammatory drugs; PLA2—phospholipase A2; PGD2—prostaglandin D2; PGE2—prostaglandin E2; PGD2‐inh—prostaglandin D2 inhibitors; PUFA—polyunsaturated fatty acids; and TSLP—thymic stromal lymphopoietin

FIGURE 3

Non‐steroidal anti‐inflammatory drugs and leukotriene antagonists in SARS‐CoV‐2 infection. Increased levels of eicosanoids have been found in bronchoalveolar lavage fluid of patients with severe COVID‐19, with predominance of prostaglandins and thromboxane. There are strong grounds to explore eicosanoid inhibition as a potential therapeutic target in SARS‐CoV‐2 infections. Prostaglandins amplify innate immune responses to pathogen‐ and damage‐associated molecular patterns, enhance the cascade of proinflammatory cytokine release, activate Th1 and Th17 cells, and contribute to recruitment of macrophages and T cells. Moreover, studies in mouse adapted to SARS‐CoV‐2 infection showed that PGD₂ inhibition protected from severe disease. Despite the initial mixed reports on the use of NSAIDs in COVID‐19, it has been concluded that these medications can be safely used to alleviate the symptoms of SARS‐CoV‐2 infection. This effect is attributed to the disruption of inflammatory circuits. Other effects of NSAIDs in COVID‐19 are being investigated, and preliminary studies suggest that a non‐selective NSAID naproxen could negatively influence SARS‐CoV‐2 replication. Furthermore, the efficacy of leukotriene antagonist montelukast is being evaluated in a series of clinical trials. The hypothesized mode of action in COVID‐19 includes inhibition of leukotriene signaling, as well as direct antiviral effect (damage to the viral lipid membrane and genome), as reported for other viruses

FIGURE 4

Interactions of endocannabinoid with arachidonic acid metabolism and effects of non‐steroidal anti‐inflammatory drugs (NSAIDs). Main endocannabinoids in humans include arachidonyl‐ethanolamide (AEA) and 2‐arachidonoyl‐glycerol (2‐AG). AEA can be obtained from N‐acyl‐phosphatidylethanolamine (NAPE) via hydrolysis or by conjugation of ethanoloamine and arachidonic acid (AA). AEA can be also hydrolyzed to AA by the fatty acid amide hydrolase (FAAH). FAAH might be inhibited by NSAIDs. 2‐AG comes from diacylglycerol (DAG) through the actions of DAG lipase (DAGL). 2‐AG can be also hydrolyzed by monoacylglyserol lipase (MGL) to AA. Endocannabinoids also metabolized by eicosanoid biosynthetic enzymes including COX2, 12‐LOX, 15‐LOX, and cytochrome P450. The NSAIDs inhibiting COX2 can enhance endocannabinoid levels and reduce AEA‐ and 2‐AG‐derived prostaglandins. COX—cyclooxygenase; Cyt—cytochrome; EET—epoxyeicosatrienoic acid; HETE—hydroxyeicosatetraenoic acid; LOX—lipoxygenase; PLA—phospholipase; and PG—prostaglandin

FIGURE 5

Effect of biologicals used in the treatment of allergic diseases on eicosanoid pathways. Biologicals have revolutionized therapeutic algorithms for patients with the most severe form of allergic diseases. Currently, 5 monoclonal antibodies have been approved for the treatment of severe asthma. Their use has been associated with a decrease in the concentration of proinflammatory lipid mediators. This is most probably an indirect effect of inhibition of immune cells which are the main eicosanoid producers in allergic inflammation. Omalizumab (anti‐IgE) binds to free IgE and inhibits their binding to IgE receptors, which results in a downregulation of FcεRI expression on mast cells, basophils, and dendritic cells. This leads to a significant decrease in biosynthesis and release of proinflammatory eicosanoids from these cells, and prevents expansion of eosinophils and ILC2. Dupilumab (anti‐IL‐4Rα) binds to the α subunit of the IL‐4 receptor, which is shared by IL‐4 and IL‐13 receptor complexes. Therefore it blocks the effect of these cytokines on cells contributing to type 2 immune reaction. This results in an inhibition of IgE production, mast cell activation and eicosanoid production, goblet cell metaplasia, and mucus production. Mepolizumab, reslizumab (anti‐IL‐5), and benralizumab (anti‐IL‐5Rα) block IL‐5 activity on different levels, therefore inhibiting the maturation, activation, and proliferation of eosinophils, as well as basophil activation. Monoclonal antibodies targeting IL‐5Rα moreover lead to antibody‐dependent cell‐mediated cytotoxicity of NK cells against eosinophils and basophils, vast producers of proinflammatory eicosanoids such as prostaglandin D₂ and cysteinyl leukotrienes. While no direct effect of biologicals on eicosanoid biosynthesis has been reported, these medicines disrupt the cascade of immune events leading to type 2 inflammatory responses and the concomitant overproduction of proinflammatory lipid mediators