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
SOKOLOWSKA et al.
Swiss Institute of Allergy and Asthma Research (SIAF) University of Zurich Davos Switzerland
Christine Kühne ‐ Center for Allergy Research and Education (CK‐CARE) Davos Switzerland
Department of Pharmaceutical Sciences Section of Pharmacology and Biosciences University of Milan Milano Italy
Department of Respiratory Medicine and Allergology Skane University Hospital Lund Sweden
Department Microbiology Immunology and Transplantation Ku Leuven, Catholic University of Leuven Belgium
Department of Respiratory Medicine First Faculty of Medicine Charles University and Thomayer Hospital Prague Czech Republic
Institute of Pathophysiology and Allergy Research Center for Pathophysiology, Infectiology and Immunology Medical University of Vienna Vienna Austria
Child Life and Health and Centre for Inflammation Research The University of Edinburgh Edinburgh UK
VIB Center for Inflammation Research Ghent University Ghent Belgium
London North Genomic Laboratory Hub Great Ormond Street Hospital for Children NHS Foundation Trust London UK
Department of Biochemistry and Molecular Biology School of Chemistry Complutense University Madrid Spain
Departments of Medicine and Microbiology APC Microbiome Ireland University College Cork Cork Ireland
Department of Pulmonology and Phthisiology Department of Allergology and Clinical Immunology Department of Pediatrics Jessenius Faculty of Medicine in Martin Comenius University in Bratislava University Teaching Hospital in Martin Slovakia
Department of Otorhinolaryngology, Head and Neck Surgery Section of Rhinology and Allergy University Hospital Marburg Philipps‐Universität Marburg Marburg Germany
Allergy Unit Málaga Regional University Hospital‐IBIMA‐UMA Málaga Spain
Department of Medicine Jagiellonian University Medical College Krakow Poland
Institute of Environmental Medicine and the Centre for Allergy Research, Karolinska Institute, and the Department of Respiratory Medicine Karolinska University Hospital Stockholm Sweden
Asthma UK Centre in Allergic Mechanisms of Asthma School of Immunology and Microbial Sciences King's College London London UK
* CorrespondenceMilena Sokolowska, Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Herman‐Burchard‐Strasse 9, CH‐7265 Davos‐Wolfgang.
Email: milena.sokolowska@siaf.uzh.ch
Grzegorz Woszczek, Asthma UK Centre in Allergic Mechanisms of Asthma, School of Immunology and Microbial Sciences, King's College London, 5th Floor, Tower Wing, Guy's Hospital, London SE1 9RT, UK.
Email: grzegorz.woszczek@kcl.ac.uk
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.
Article notes
Sokolowska M , Rovati GE , Diamant Z , et al. 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. Allergy. 2022;00:1–18. doi:10.1111/all.15258 PMC911141335174512
Footnote Group
1INTRODUCTION
Non‐steroidal anti‐inflammatory drugs (NSAIDs) and other eicosanoid pathway modifiers are one of the most frequently used anti‐inflammatory medications worldwide against symptoms of infections, other acute and chronic inflammatory diseases, and pain. Eicosanoids, including prostaglandins (PGs), leukotrienes (LTs), thromboxanes (TXs), hydroxyeicosatetraenoic acids (HETEs), lipoxins (LXs), and many recently proposed pro‐resolving mediators constitute a wide range of active lipid mediators possessing pro‐ and anti‐inflammatory, as well as pro‐resolution properties. 1 They are products of the major unsaturated fatty acids: arachidonic acid (AA), dihomo‐γ‐linolenic acid (DHGLA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), metabolized in three main pathways: cyclooxygenase (COX), lipoxygenase (LO or LOX), and cytochrome P450 (Figure 1). Those active lipid mediators play substantial roles in the development and resolution of inflammation, including allergic and viral inflammation, which we have reviewed extensively in the previous report. 1 Even though NSAIDs and other eicosanoid pathway modifiers are so commonly consumed and are relatively safe for the majority of people, the current pandemic of the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) revealed substantial knowledge gaps in understanding their modes of action, benefits, and risks related to their use in patients with respiratory and allergic diseases. Unfortunately, this resulted in the conflicting messages sent to the public from the scientific community. Therefore, we, the European Academy of Allergy and Clinical Immunology Task Force (EAACI TF) on Eicosanoids, here critically review the most recent findings on the roles of NSAIDs, leukotriene antagonists (LTRAs), prostaglandin D2 (PGD2) receptor antagonists, and cannabinoids, as well as we summarize their selectivity, and additional modes of actions in allergic airway diseases, drug allergy, and respiratory virus infections. In addition, we also describe here the effects of novel T2 biologicals used in allergic diseases on eicosanoid pathways.
2NSAIDS IN ASTHMA AND VIRAL ASTHMA EXACERBATIONS
Aside from NSAIDs‐exacerbated respiratory disease (NERD), NSAIDs are usually well tolerated by patients with asthma, and therefore, they are often used in real life against symptoms of respiratory infection such as fever and pain, even during asthma exacerbations together with intensified asthma treatment in children and adults. 2 Current Global Initiative for Asthma (GINA) guidelines are stating with evidence level A, that aspirin and other NSAIDs are generally not contraindicated in patients with asthma, unless there is a history of previous reactions to those medications. Nevertheless, it is still not very well studied whether NSAIDs facilitate or inhibit achievement of asthma control following exacerbations, and if they affect the speed of resolution of airway inflammation. Exacerbations of asthma are most often induced by common respiratory viruses including rhinovirus (RV), respiratory syncytial virus (RSV), bocavirus, influenza viruses, adenovirus, and others. 3 , 4 , 5 RV is responsible for up to 76% of exacerbations of wheeze in children and up to 83% of asthma attacks in adults. 3 , 4 , 5 Recurrent viral infections do not only cause acute disease and exacerbations of established disease, but they also contribute to the pathophysiology of early wheezing in children and the development of asthma. Prophylaxis of RSV‐induced bronchiolitis with palivizumab, an anti‐RSV monoclonal antibody, in late pre‐term infants decreased the risk of recurrent infant wheeze and the rate of parent‐reported asthma symptoms at 6 years of age, however, without any effect on lung function or doctor‐diagnosed asthma. 6 , 7 The majority of respiratory viruses are known to modify several major eicosanoid pathways, including the COX and the LOX pathways 8 (Figure 2). RV infection increases expression of 5‐lipoxygenase (5‐LOX), 5‐lipoxygenase activating protein (FLAP), and cyclooxygenase‐2 (COX‐2), as well as the production of prostaglandins E2 (PGE2) and PGD2 by the respective isomerases in human bronchial epithelial cells, with higher levels in asthmatic patients than in controls. 9 In addition, cysteinyl leukotriene (cysteinyl‐LT) levels, 5‐LOX‐positive cells, and FLAP‐positive cells in bronchoalveolar lavage fluid are increased in humans upon RV infection and correlate with the emergence of upper respiratory symptoms. 10 Infection with RV affects airway mucosal barriers and also the peripheral blood and distant tissues. PGE2 plays an important role in optimal antibody synthesis, as COX inhibitors reduce antibody release by plasma cells, also in case of viral infections. 11 , 12 Healthy individuals experimentally infected with RV showed a suppressed serum neutralizing antibody response when treated with aspirin or acetaminophen. 13 Significant increase in COX‐2 (PTGS2) expression and in COX‐derived metabolites is a hallmark of RSV 14 and influenza virus infection. 15 Pharmacologic inhibition of the COX pathway decreased RSV‐induced lung pathology, although this was not linked to a specific metabolite. 14 , 16 At a later stage of RSV infection there is an increase in LOX metabolites, which might promote appropriate resolution of infection‐induced inflammation. 17 This resolution is impaired in 5‐LOX and 15‐LOX knockout mice upon RSV or pathogenic influenza strain infection. Moreover, in mice lacking 5‐LOX, there is an upregulation of COX2 expression and aggravation of infection‐induced lung pathology. 14 , 16 During influenza A infection, newly generated PGE2 leads to the inhibition of type I interferon (IFN) production, inhibition of macrophage apoptosis, and subsequent increase in virus replication. Ptges −/− knockout mice, which do not produce PGE2, or wild‐type mice treated with PGE2 type 2 (EP2) and type 4 receptor (EP4) antagonists demonstrated enhanced protection against lethal influenza infection. 18 PGE2 also inhibits activation of the Nod‐like receptor family pyrin domain containing 3 (NLRP3) inflammasome in human monocytes and macrophages, and COX pathway blocking increases inflammasome activation and mature Il‐1β release. NLRP3 inflammasome activation can contribute to limiting viral replication at the early stages of infection, but in some instances, it may also lead to harmful hyperinflammation during late‐stage infection. 19 Much less is known about PGD2 and antiviral responses. However, it was shown that in aging mice there is an increase in PGD2 in the lungs which correlates with the impaired migration of respiratory dendritic cells (DC) to lymph nodes, diminished T‐cell responses, and more severe clinical disease in older mice infected with respiratory viruses, such SARS‐CoV‐1 and influenza. 20 Blocking PGD2 function enhances DC migration, T‐cell responses, and survival in the infected animals. 20 In summary, prostaglandins and other COX‐dependent metabolites are involved in a complex way in the pathogenesis of respiratory viral infections and thus in virus‐induced exacerbation of asthma. Therefore, the use of NSAIDs to alleviate symptoms of viral infections in general population and in patients with asthma should be re‐evaluated with assessment of the effects of the timing of the administration, their selectivity, and the long‐term effects.
3NSAIDS IN COVID‐19
NSAIDs are used worldwide to alleviate symptoms of viral infections and inflammation, such as fever, cough, and pain. Since NSAIDs inhibit COX‐1 and COX‐2 and thus decrease the release of many downstream lipid mediators, such as various PGs, prostacyclin, and TXs, they have very broad effects on inflammation and immune responses, ranging from anti‐inflammatory, immunosuppressive, and anti‐thrombotic to pro‐resolving (Figure 2). 1 , 21 Therefore, at the beginning of the COVID‐19 pandemic, there were several concerns and uncertainties about the effects of NSAIDs on SARS‐CoV‐2 infection and the course of COVID‐19. 22 They were suspected to alter the expression of angiotensin‐converting enzyme 2 (ACE2), the main entry receptor for SARS‐CoV‐2 and/or modify viral replication. 23 , 24 , 25 , 26 In addition, they could be either harmful by impairing antiviral response and delaying resolution of inflammation 15 , 18 , 27 , 28 or be beneficial by dampening of hyperinflammation and cytokine storm 29 , 30 and preventing thrombosis 31 , 32 (Figure 3). Some of these concerns have now been addressed experimentally and epidemiologically, and several clinical trials have been initiated. Indeed, SARS‐CoV‐2 increases PTGS2 (COX‐2) gene expression in variety of cell lines, in mouse lungs and in primary human bronchial epithelial cells as well many eicosanoids and docosanoids are increased in the lungs of severe COVID‐19 patients. 33 , 34 , 35 However, inhibition of the COX pathway by either ibuprofen (non‐selective COX1/COX2 inhibitor) or meloxicam (more selective COX‐2 inhibitor) did not change the expression of ACE2 in human cell lines (Calu‐3 or Huh7.5) in vitro or in lungs, kidney, heart, or ileum of mice in vivo. 33 Similarly, both NSAIDs did not affect SARS‐CoV‐2 entry or its replication in the same human cell lines. 33 Aspirin also did not affect ACE2 or transmembrane serine protease 2 (TMPRSS2) expression in human nasal epithelium. 36 Meloxicam also did not prevent SARS‐CoV‐2‐infection‐induced weight loss in mice and did not change frequencies or activations status of alveolar macrophages, neutrophils, NK cells, Ly6C+ Mo/Mθ, CD4+ T cells, CD8+ T cells, and γδ T cells. However, meloxicam treatment decreased the amount of spike‐specific IgM and IgG antibodies and their neutralizing capacities as well as decreased infection‐induced levels of IL‐6, CCL2, GM‐CSF, CXCL10, IL‐2, and TNF‐α, suggesting that while meloxicam can impair humoral immune response against SARS‐CoV‐2 to some extent, it might also limit levels of proinflammatory cytokines. 33 In contrast, naproxen, which is a non‐selective COX‐1/COX‐2 inhibitor, has been shown to bind to the nucleocapsid protein N of SARS‐CoV‐2, which led to inhibition of SARS‐CoV‐2 replication in VeroE6 cells and primary human bronchial epithelial cells and protected epithelium against SARS‐CoV‐2‐induced barrier damage. 37 There were no analogous effects in similar experiments with paracetamol (acetaminophen, which may affect PG production in the brain or may act via its metabolite on the cannabinoid receptors), 38 , 39 or celecoxib (selective COX‐2 inhibitor). 37 Naproxen is currently examined in the clinical trial in COVID‐19 (eudract_number:2020‐001301‐23; accessed 11.06.2021). So far, in various patient groups, it has been shown that usage of NSAIDs does not lead to the worse COVID‐19 outcomes. 40 In a retrospective study of 403 confirmed cases of COVID‐19, there were no differences in terms of mortality rate or need for respiratory support between patients who were taking ibuprofen or those who did not take any NSAIDs. 41 It was also confirmed in the large prospective cohorts that either acute or chronic use of NSAIDs was not associated with worse COVID‐19 outcomes. 42 , 43 , 44 It was even shown that in patients, who were treated with aspirin or other NSAIDs due to the cardiovascular diseases, positive aspects of such therapies have been noted, including reduction of COVID‐19 mortality. 31 This clinical observation is further supported by a study on COX‐2 induction and PGE2 overproduction in the human lung infected by SARS‐CoV‐2. 45 However, further basic in vitro, in vivo, and large clinical studies assessing the influence of NSAIDs on the pathogenesis and treatment of COVID‐19 are still greatly needed.
4LEUKOTRIENE RECEPTOR ANTAGONISTS—NOVEL MECHANISMS OF ACTION
All clinically available LTRAs (montelukast, zafirlukast, and pranlukast) act on the cysteinyl leukotriene type 1 receptor (CysLT1) and by competitive antagonism at this receptor are believed to be responsible for the control of airway inflammation, bronchoconstriction, and remodeling. 46 , 47 , 48 However, anti‐inflammatory activity of LTRAs independent of CysLT1 antagonism has been suggested. LTRAs reduced the eosinophil protease activity 49 and inhibited TNFα‐ 50 or UDP‐mediated 51 , 52 cytokine expression, as well as NF‐κB activation in human mononuclear 53 or epithelial cells 54 through processes that appear to be distinct from CysLT1 antagonism. Although mechanisms of these non‐CysLT1‐related LTRA activities are not fully understood, concentration‐dependent inhibition of distinct receptors such as P2Y1, P2Y2, P2Y6, and GPR17 by LTRAs have been reported, 51 , 52 , 55 suggesting, at least for P2Y receptor, a non‐competitive mechanism of action. Interestingly, it was also shown that LTRAs may have a potent inhibitory effect on 5‐LOX activity (i.e., LT production) 52 , 56 and transport of LTs by the multidrug resistance protein ABCC4, 57 suggesting a much broader mechanism of action for these drugs than previously suspected. Indeed, non‐CysLT1‐related mechanisms of LTRA might represent another level of variability in the response to treatment in patients with asthma and allergy. Some of these activities may be compound‐specific or may depend on drug concentration (most non‐CysLT1‐related effects required micromolar drug concentrations 51 , 52 , 53 in contrast to nanomolar levels needed for CysLT1 antagonism 58 , 59 , 60 ) or may depend on the presence of a particular inflammatory pathway in patients with asthma (allergy), and therefore, clinically significant effects of treatment may be observed in some, but not all, treated patients. It should be emphasized that initial clinical interventional studies of montelukast in asthma used doses up to 200 mg a day 61 , 62 showing greater lung function improvement than in subsequent studies using recommended dose of 10 mg, 63 suggesting that higher doses of currently known LTRAs or new compounds derived from this class of drugs may represent a novel strategy for finding more efficient therapy. The demonstration that the bronchoconstrictive actions of LTE4 in asthma are solely mediated by the CysLT1 receptor further supports that effects on other targets than the CysLT receptors may take place 64
5PREDICTING RESPONSES TO LTRA THERAPY
Heterogeneous effects of LTRA therapy in asthma and allergic diseases have been reported in many studies. Although some genetic 65 , 66 and acquired factors have been suggested, 67 other reasons for this heterogeneity remain unclear. While currently no clinical characteristics or laboratory assay can reliably predict responses to LTRAs, the most plausible biomarker that could potentially serve as response predictor to LTRAs seems LTE4 production. Urinary LTE4 (uLTE4) is a biomarker of total body cysteinyl‐LT production, 1 associated with Type 2 asthma, asthma severity, exacerbations, and NERD. 68 , 69 Increased uLTE4 to fractional exhaled nitric oxide (LTE4: FeNO) ratio has been suggested to predict favorable response to LTRA therapy (montelukast) in asthmatic children, 70 , 71 but these observations have not been confirmed in adult patients. There is a considerable amount of evidence supporting the concept that some patients or clinical phenotypes seem sensitive to LTRAs, especially in a real‐life setting, due to enhanced cysteinyl‐LT production, better adherence to oral therapy or oral drug delivery. LTRAs have proven to be particularly effective in exercise‐induced asthma, 72 asthma associated with allergic rhinitis, 73 NERD, 74 viral‐induced wheezing episodes, 75 and patients having difficulties with inhaled therapy such as children and elderly. 76 , 77 Cigarette smoking while inhibiting steroid anti‐inflammatory responses 78 increases cysteinyl‐LT production, 79 leading to a greater response to montelukast in smokers with asthma, suggesting that LTRA could be more effective in treating such individuals. 80 In fact, asthmatic patients with smoking history above 11 pack‐years showed more benefit with montelukast treatment than inhaled steroids. 81 Obesity is another potential risk factor for asthma development and efficacy of treatment. Interestingly, higher body mass index (BMI) is associated with increased LT production in asthmatics 82 and as therapeutic response to inhaled corticosteroids decreases with increasing BMI, response to montelukast remains unaffected, 83 suggesting LTRA therapy to be more effective in obese patients. The response to LTRA may also be associated with sex differences. The existence of a sex bias in LT biology is already suggested by the fact that many LT‐related diseases including asthma, allergic rhinitis, rheumatoid arthritis, or NERD have a higher occurrence in women compared to men, pointing to more pronounced pathophysiological roles of LTs in females. 84 , 85 Furthermore, several observations suggest that female sex is associated with higher LT biosynthesis, while androgens seem to exert a suppressing role on LT formation both in vitro and in vivo. 86 , 87 , 88 , 89 , 90 Although the clinical significance of these data is still to be confirmed, in a small prospective cohort study, montelukast showed superior effects on symptoms and lung function in women compared to men, 91 while a tendency for a better response to montelukast was evident in girls exposed to tobacco smoke. 92
7PGD2 RECEPTOR ANTAGONISTS
In sensitized subjects, PGD2 is initially released by allergen‐triggered mast cells and plays a key role in the sequelae of the allergic response. Its proinflammatory effects are mediated through the interaction with G‐protein‐coupled receptors (GPCR): DP1, thromboxane (TP), and chemoattractant‐homologous receptors (CRTH2 or DP2). 113 Apart from its broncho‐ and vaso‐active properties in allergic airway disease, PGD2 also acts as an important link between the allergen‐induced early (EAR) and late phase allergic response (LAR) through the interaction with the DP2‐receptors on key effector cells. DP2‐receptors are expressed on immune (ILCs, Th2), inflammatory (eosinophils, basophils), and structural (epithelial) cells and involved in the recruitment and activation of these cells as well as the subsequent release of Th2‐cytokines during the LAR. 113 , 114 , 115 , 116 Therefore, DP2 (CRTH2) antagonists have been initially aimed for the treatment of allergic airway disease (allergic rhinitis, asthma). 117 , 118
In two proof‐of‐concept studies in (unphenotyped) allergic asthmatics, DP2 (CRTH2) antagonists (timapiprant and setipiprant, respectively) showed only modest reduction (approx. 25%) in the allergen‐induced LAR 119 , 120 while no convincing effects were observed on the allergen‐induced changes in T2 biomarkers (blood eosinophils, FeNO) 120 with only a minimal reduction in sputum eosinophils post‐allergen. 119 In addition, there was no decrease in the EAR in either study. The (relative) lack of protection against allergen‐induced airway responses may (partly) consist with the fact that even with effective DP2‐blockade, an allergen‐triggered mast cell (lacking DP2) 121 mediator release (histamine, PGD2, cysteinyl‐LTs) may still occur which is capable of causing an EAR and/or an LAR 122 , 123 and therefore, especially in allergic asthma, a combined blockade of, for example, DP2 ± DP1 ± TP ± cysteinyl‐LT‐R might provide a superior protection.
In line with this reasoning—and despite prior evidence of superior efficacy in phase 2B studies of patients with an allergic (T2‐) profile (atopy ± eosinophils ≥250/mcL) 124 , 125 —several DP2 (CRTH2) antagonists (e.g., setipiprant, fevipiprant) failed in phase 3 clinical trials of allergic airway disease. 125 More recently, DP2‐blockade has been associated with the reduction in airway smooth muscle mass by decreasing airway eosinophilia and the recruitment of myofibroblasts and fibrocytes. 126 Therefore, with several clinical trials still ongoing, (add‐on) DP2‐blockade may show efficacy in more severe T2 asthma 127 and related conditions based on its anti‐inflammatory and disease‐modifying potential. 126 , 128
Respiratory viruses (e.g., RSV) represent other important triggers of chronic inflammatory airway disease capable of activating the PGD2/DP2 receptor‐mediated pathway, thereby eliciting a “non‐allergen‐induced” T2‐immune response through airway epithelial cells and innate immune cells. 129 Indeed, RSV has been associated with upregulation of the PGD2/DP2 pathway and increased PGD2 levels both in experimental and in clinical studies, while DP2‐blockade alone or combined with DP1 agonism showed protective potential in preclinical studies. 130 Therefore, selective targeting of PGD2 receptors has been postulated to protect against respiratory viral infections, and more recently, including SARS‐CoV‐2. 131 Presently, this hypothesis awaits clinical evidence. In addition, the potent bronchoconstrictive actions of PGD2 and other constrictive prostanoids in human airways call for trials with TP receptor antagonists in patients with asthma 132
8CANNABINOIDS IN ASTHMA, ALLERGIC DISEASES, AND VIRAL INFECTIONS
The human endogenous cannabinoid system (ECS) is involved in many physiological processes. It consists of the cannabinoid receptors (CBRs), the endogenous ligands (anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG)), and the proteins related to their synthesis and degradation. 133 Cannabinoid receptor 1 (CB1) and 2 (CB2) are the main CBRs. CB1 is largely expressed in the central nervous system but also in peripheral tissues and immune cells. CB2 is mainly expressed in immune cells but also in other cell types such as progenitor neurons. 134 , 135 The biosynthesis and inactivation of endocannabinoids involve several enzymes. AEA can be synthetized by the hydrolysis of its precursor N‐acyl‐phosphatidylethanolamine (NAPE) by NAPE‐hydrolyzing phospholipase D (NAPE‐PLD). Alternative pathways involving other phospholipases have been described. AEA can be also obtained from the reverse reaction of fatty acid amide hydrolase (FAAH) by the conjugation of ethanolamine and AA. The main pathway for the synthesis of 2‐AG is the hydrolysis of AA‐containing 1,2‐diacylglycerol (DAG) species by DAG lipase‐α or β. 133 , 136 Endocannabinoids are rapidly metabolized. The hydrolysis of AEA is mediated by FAAH, whereas 2‐AG is hydrolyzed by monoacylglycerol lipase (MGL). The resulting products of AEA and 2‐AG degradation are AA, and ethanolamine and glycerol, respectively (Figure 4).. 133 , 136 Moreover, endocannabinoids are susceptible to be metabolized by eicosanoid biosynthetic enzymes including COX2, 12‐LOX, 15‐LOX, and P450. 136 FAAH and MGL are considered promising therapeutic targets for the treatment of several disorders, including inflammation. Pharmacological inhibitors of FAAH and MGL increase the levels of AEA and 2‐AG, prolonging their anti‐inflammatory effects, and decrease AA levels. 137 , 138 The NSAIDs that inhibit COX2 also enhance endocannabinoid levels and reduce AEA‐ and 2‐AG‐derived prostaglandins. 139 , 140 In addition, some NSAIDs such as ibuprofen can influence the endocannabinoid levels by inhibiting FAAH (Figure 4).
The role of cannabinoids in allergic diseases is still a bit controversial. 141 Sukawara et al demonstrated that endocannabinoids limited mast cell maturation and activation in human airway mucosa and skin through CB1. 142 , 143 Tetrahydrocannabinol (THC) and cannabidiol (CBD) attenuated airway allergic inflammation, decreased cytokine production, cell infiltration, mucus secretion, and bronchial hyperresponsiveness in mice. 144 , 145 , 146 Similarly, the synthetic agonist CP55,940 induced lung protection in ovalbumine (OVA)‐induced asthma guinea pig models via CB1 and CB2. 147 In keratinocytes, CB1 prevented transepithelial water loss and skin inflammation, cell infiltration and cytokine production in atopic dermatitis mouse model. 148 Anandamide and different CB1 agonists also accelerated skin barrier recovery and reduced proinflammatory cytokine production and cell recruitment. 149 , 150 Several cannabinoids have also shown a protective role in allergic contact dermatitis by reducing inflammatory responses. 151 , 152 , 153 CB1 activation may also induce bronchodilation in the airways. 147 , 154 In human bronchial epithelial cells, the synthetic agonist WIN55212‐2 restored the epithelial barrier disruption induced by RV. 155 In addition, WIN55212‐2 decreased the immediate anaphylactic reaction in a mouse model of peanut allergy and promoted the generation of allergen‐specific regulatory T cells. 156 Currently, different studies suggest the therapeutic potential of cannabinoids in COVID‐19 pandemic. 157 , 158 , 159 In contrast, Frei et al showed that CB2 activation enhanced migratory responsiveness of eosinophils in an OVA‐asthma mouse models. 160 Accordingly, the lack of CB2 decreased allergic inflammation in asthma and dermatitis mouse model. 161 This result correlated with increased number of NK cells and reduced number of ILC2s in the lung of CB2 knockout mice, demonstrating that NK cells are negative regulators of ILC2s. 162 Interestingly, it has been described that mRNA expression levels of CB1 are upregulated in tonsils and peripheral blood of patients with allergic rhinitis, atopic dermatitis, and food allergy, but the functional relevance remains unknown. 163 These studies suggest that the ECS could be explored as a potential therapeutic target in the treatment of asthma, allergic and skin diseases, and viral infections.
9THE EFFECT OF T2‐TARGETED BIOLOGICALS ON EICOSANOIDS
Ample evidence from clinical trials showing effectiveness of drugs targeting T2‐inflammation (targets include IgE and the cytokines IL5, IL4, and IL13) on asthma exacerbations, as well as improvements in symptoms and disease severity in chronic rhinosinusitis with nasal polyps (CRSwNP), 164 , 165 underscored the involvement of T2‐inflammation in these conditions. 166 , 167 As mentioned above, the majority of asthma exacerbations are precipitated by respiratory viruses (esp. RSV and RV), 168 while in sensitized subjects, allergen exposure may enhance virally triggered exacerbations due to synergistic interaction through joint mechanisms including the T2‐inflammatory pathway. 168 , 169 , 170 , 171 Both viral and allergen‐triggered pathways include several inflammatory and immune (effector) cells, such as mast cells, basophils, Th2 cells, ILCs, macrophages, neutrophils, and eosinophils. Many of these cells are capable of releasing eicosanoids upon activation and/or possess one or more eicosanoid receptors, 172 thus contributing to the exacerbation and its sequelae (e.g., bronchoconstriction, airway inflammation, and bronchial hyperresponsiveness). 173 In CRSwNP, the T2‐inflammatory pathway is also triggered by several stimuli such as viruses, bacteria, and allergens, which stimulate inflammatory cell‐ and cytokine‐mediated pathomechanisms in the nasal and paranasal mucosa. 167
Although in vitro data indicate that biologicals may influence eicosanoid pathways in mast cells and basophils, 174 so far there are no published data on direct effects of T2‐targeted biologicals on the synthesis or release of eicosanoids in humans in vivo (Figure 5). However, it makes sense that, by blocking pathways and cells (esp. mast cells, basophils, eosinophils, and neutrophils) responsible for the release of these proinflammatory mediators, may consequently also reduce eicosanoid levels. In addition, previous evidence from clinical studies in asthma showed (partial) reduction of both allergen‐ and virus‐induced airway responses and asthma exacerbations by selective eicosanoid antagonists. 48 , 119 , 120 , 175 , 176 , 177 Besides, clinical studies on biologicals in CRSwNP also included a representative cohort of patients with NERD and also found a good clinical response 164 and a reduced T2‐biomarker profile in this subpopulation. 178 However, so far there are no data on the direct effect of T2 biologicals on the individual eicosanoids nor head‐to‐head studies comparing biologicals with selective eicosanoid blockers or combinations.
10NSAID‐EXACERBATED RESPIRATORY DISEASE (NERD). SELECTIVITY OF NSAIDS
NERD, also called AERD‐aspirin‐exacerbated respiratory disease or AIA‐aspirin‐intolerant asthma, is a phenotype of asthma recognized in 5 to 25% asthmatics. It is characterized by a non‐immunological hypersensitivity to low doses of NSAIDs and a cross‐reactivity (a multi‐responder phenotype). Profound changes in biosynthesis of eicosanoids comprise overproduction of cysteinyl‐LTs, excreted in urine as LTE4. 179 , 180 Some patients have higher excretion of LTE4 also during a stable period of NERD. 74 , 181 , 182 , 183 It is debatable, which cells produce cysteinyl‐LTs in NERD. Since overproduction of PGD2 and increase of histamine concentration accompany symptoms of NERD, these could be mast cells. However, eosinophils in NERD overexpress leukotriene C4 synthase (LTC4S), thus can contribute to the symptoms and concurrent release of eosinophils cationic protein was observed. PGE2 plays a key role in NERD, where both decreased production of PGE2 and reduced EP2 expression were observed. 180 , 184 When PGE2 is further decreased, it leads to mast cell activation and bronchoconstriction because it removes the stabilizing effect of PGE2 on mast cell mediator release. 132 Accordingly, inhalation of PGE2 before aspirin challenge prevented reduction in pulmonary function and mast cell activation. 185 However, inhibition of PGE2 biosynthesis by NSAIDs is difficult to measure, since this prostaglandin is produced by most cells of the body. Interestingly, patients with NERD have also an imbalance in pro‐resolving lipoxin A4 (LXA4) that may contribute to the increased severity of this particular asthma endotype. 186 The minimal dose triggering bronchial constriction and extra bronchial symptoms (cutaneous flush, nasal obstruction, irritations of conjunctiva) varies across patients, but generally it reflects NSAID potency to inhibit cyclooxygenase‐1 isoenzyme (COX‐1). 187 , 188 Highly selective inhibitors of COX‐2 like coxibs (e.g., celecoxib, etoricoxib) 189 are well tolerated in most NERD patients, whereas preferential COX‐2 inhibitors (nimesulide, meloxicam) can trigger symptoms at high doses 190 (Table 1). Diclophenac, ketorolac, ibuprofen, naproxen, indomethacin, or pyrazolone derivatives inhibit both COX‐2 and COX‐1, 191 therefore are contraindicated in NERD. Acetylsalicylic acid is more potent inhibitor of COX‐1 than COX‐2. 189 , 192 This was the first NSAID ever reported to trigger symptoms in asthmatics. Paracetamol (acetaminophen), with an unclear effects on prostanoids biosynthesis including possible inactivation of brain cyclooxygenases by a non‐substrate mechanism, is tolerated by the vast majority of NERD patients unless given in very high doses. 39
| Drug | Group | Target | Remarks | References |
|---|---|---|---|---|
| Ketoprofen | NSAID | COX‐1 >> COX‐2 | 204 | |
| Aspirin | NSAID | COX‐1 >> COX‐2 | 192 | |
| Naproxen | NSAID | COX‐1, COX‐2 | 204 | |
| Ibuprofen | NSAID | COX‐1, COX‐2 | 204 | |
| Diclofenac | NSAID | COX‐1, COX‐2 | 191 | |
| Ketorolac | NSAID | COX‐1, COX‐2 | 205 | |
| Indomethacin | NSAID | COX‐1, COX‐2 | 206 | |
| Dipyrone (metamizole) | NSAID | COX‐1, COX‐2 | 207 | |
| Piroxicam | NSAID | COX‐2 > COX‐1 | 192 | |
| Meloxicam | NSAID | COX‐2 >> COX‐1 | 192 | |
| Nimesulide | NSAID | COX‐2 >> COX‐1 | 189 | |
| Celecoxib | NSAID | COX‐2 >> >COX‐1 | 189 | |
| Etoricoxib | NSAID | COX‐2 >> >COX‐1 | 189 | |
| Paracetamol (acetaminophen) | Related to NSAIDs | COX‐1, COX‐2‐non‐substrate mechanism | 38, 39 | |
| Montelukast | LTRA | CysLTR1 | Additional immunomodulatory properties have been suggested | 46 |
| Zafirlukast | LTRA | CysLT1 | 46 | |
| Pranlukast | LTRA | CysLT1 | 46 | |
| Zileuton | Leukotriene synthesis inhibitor | 5‐LOX | 208 | |
| Fevipiprant | Prostaglandin receptor antagonist | DP2 | Phase 3 clinical trials | 209 |
| Asapiprant | Prostaglandin receptor antagonist | DP1 | Phase 2 clinical trials | ClinicalTrials.gov Identifier: NCT04705597 |
| Laropiprant | Prostaglandin receptor antagonist | DP1 | Temporarily approved in Europe as a component of a hypolipidemic drug | 210 |
| Vidupiprant | Prostaglandin receptor antagonist | DP2 > DP1 | Phase 2 clinical trials | ClinicalTrials.gov Identifier: NCT01018550 |
11EICOSANOIDS IN DRUG ALLERGY
Most of the information available on the role of eicosanoids in allergy and related diseases concerns NERD. 193 , 194 This fact can be explained because it was the first clinical phenotype in which a link between NSAIDs pharmacological activity and the inhibition of PGE2 synthesis by blocking COX‐1 and the subsequent increase in cysteinyl‐LTs release was established. 195 Nevertheless, some data are also available for cutaneous NSAID‐induced cross‐hypersensitivity. Thus, increased LTE4 and 9α,11β‐PGF2 urinary levels have been described for NERD 196 , 197 , 198 , 199 and for NSAID‐induced acute urticaria/angioedema (NIUA). 199
For NSAID‐exacerbated cutaneous disease (NECD), contrasting results have been found regarding eicosanoids levels at basal state. Thus, Di Lorenzo et al. did not report baseline differences for LTE4 in patients with chronic urticaria and hypersensitivity to acetylsalicylic acid (ASA, aspirin) or food additives, 200 and no variations at basal state were reported for LTE4 and 9α,11β‐PGF2 by two other independent studies. 197 , 199 However, Mastalerz et al. reported increased LTE4 levels in NECD patients with a positive aspirin challenge with respect to those with a negative aspirin challenge, and with no changes found for 9α,11β‐PGF2. 201 It has been recently published that NIUA and NECD showed similar increased levels in both LTE4 and 9a,11b‐PGF2 within the first 3 hours following a positive aspirin challenge; however, after this time interval, these mediators showed different behaviors, being such levels long‐lasting in NECD. 199 In spite of these differences being not statistically significant, the reasons explaining the existence of these particular profiles are at present unknown although they may be due to the presence of additional factors in NECD, which could include sensitization to autoantibodies or the existence of histamine‐releasing factors. 199
Data on the role of eicosanoids beyond NSAIDs‐hypersensitivity are scarce. However, a potential role for cysteinyl‐LTs was proposed in adverse reactions to non‐ionic contrast media. Thus, iopromide and iotrolan induced a significant increase of cysteinyl‐LTs in vivo, with no changes in preformed mediators levels. 202 However, a previous study showed the heterogeneity of the effects of contrast media on mediator release, showing an increase in histamine and tryptase release from different human cells without changes in LTE4 or PGD2 levels. 203
12CONCLUSIONS AND UNMET NEEDS
NSAIDs, LT modifiers, and biologicals are used every day in clinical practice in treatment of viral infections and common respiratory or allergic diseases. Although a significant progress has been made in our understanding how these medications act and how they affect eicosanoid pathways, there are still no sufficient data available to fully address all issues important for prediction of their activities affecting immune response and estimation of their clinical efficacy. This consensus report summarizes up to date knowledge in this complex area and identifies major knowledge gaps and unmet needs to be addressed in the future.
12.1Unmet needs
- Assessment of NSAIDs role in alleviating symptoms of viral infections in general population and in patients with asthma/ allergy with the strong emphasis on the timing of its administration, their selectivity, and long‐term effects.
- Further basic in vitro, in vivo, and large clinical studies assessing NSAIDs influence on the pathogenesis and treatment of COVID‐19 are greatly needed.
- Understanding molecular and cellular mechanisms of eicosanoids activity in immune response with focus on balance between pro‐ and anti‐inflammatory properties.
- Characterization of emerging sub‐phenotypes, and sub‐endotypes of allergic diseases (asthma, rhinitis, and NERD) and potential biomarkers for the more effective therapy using eicosanoid pathway modifying drugs (NSAIDs, LTRA, and CRTH2 antagonists)
- Evaluation of how the effectiveness of new biologicals for the treatment of allergic diseases relates to the eicosanoids.
- Re‐assessment of the effects of prostanoids in allergic and asthmatic reactions in humans by targeted intervention studies with selective inhibitors of receptors or tissue‐specific synthases.
- Development and testing of novel treatment modalities targeting lipid mediators (eicosanoids) and their receptors.
CONFLICT OF INTEREST
MiSo has received research grants from the Swiss National Science Foundation, GlaxoSmithKline, Novartis, and AstraZeneca speaker fee. ZD acted as a director respiratory/allergy for QPS‐NL (2012‐2020); she has received consulting fees from ALK, Antabio, GSK, Sanofi‐Genzyme, QPS‐NL; has participated in the speaker's bureaus of Boehringer Ingelheim, Sanofi‐Genzyme; she serves in EUFOREA as an Asthma Expert Panel Chair. OsPa has received fees for lectures and/or participation in Advisory Boards from Allergy Therapeutics, Amgen, AstraZeneca, Diater, GSK, Inmunotek SL, Novartis, Sanofi‐Genezyme, Regeneron, and Stallergenes. OP has received research grants from Inmunotek SL and Novartis SL. CA has received research grants from the Swiss National Science Foundation, Christine Kühne‐Center for Allergy Research and Education, European Commission Horizon's 2020 Framework Programme “CURE,” Novartis Research Institutes, GlaxoSmithKline and AstraZeneca. He took part in the advisory board and received research grants from GlaxoSmithKline, Sanofi/Regeneron, SciBase, and Novartis. He is the editor in chief of Allergy. LOM is a consultant to PrecisionBiotics and has received research funding from GSK and Chiesi. LOM has participated in speaker's bureau for Nestle, Nutricia, Reckitt, and Abbott. MJ has received consulting fees (ALK‐Abello, Stallergenes‐Greer, Takeda, Zentiva); honoraria for lectures, presentations (ALK‐Abello, Stallergenes‐Greer, Takeda, Zentiva, Mundipharma, AstraZeneca, SOBI, Chiesi, CSL Behring, Novartis, Benela, Pfizer, Viatris); support for attending meetings and/or travel (ALK‐Abello, Stallergenes‐Greer, Takeda, Novartis, Sanofi Pasteur) and honoraria for participation on Advisory Boards (ALK‐Abello, Stallergenes‐Greer, Chiesi, Novartis, SOBI, Pfizer, Sanofi Genzyme/Pasteur). OlPh reports grants and personal fees from ALK‐Abelló, grants and personal fees from Allergopharma, grants and personal fees from Stallergenes Greer, grants and personal fees from HAL Allergy Holding B.V./HAL Allergie GmbH, grants and personal fees from Bencard Allergie GmbH/Allergy Therapeutics, grants and personal fees from Lofarma, grants from Biomay, grants from Circassia, grants and personal fees from ASIT Biotech Tools S.A., grants and personal fees from Laboratorios LETI/LETI Pharma, personal fees from MEDA Pharma/MYLAN, grants and personal fees from Anergis S.A., personal fees from Mobile Chamber Experts (a GA2LEN Partner), personal fees from Indoor Biotechnologies, grants and personal fees from GlaxoSmithKline, personal fees from Astellas Pharma Global, personal fees from EUFOREA, personal fees from ROXALL Medizin, personal fees from Novartis, personal fees from Sanofi‐Aventis and Sanofi‐Genzyme, personal fees from Med Update Europe GmbH, personal fees from streamedup! GmbH, grants from Pohl‐Boskamp, grants from Inmunotek S.L., personal fees from John Wiley and Sons, AS, personal fees from Paul‐Martini‐Stiftung (PMS), personal fees from Regeneron Pharmaceuticals Inc., personal fees from RG Aerztefortbildung, personal fees from Institut für Disease Management, personal fees from Springer GmbH, personal fees from AstraZeneca, personal fees from IQVIA Commercial, personal fees from Ingress Health, outside the submitted work; and member of EAACI Excom, member of ext. board of directors DGAKI; coordinator, main or co‐author of different position papers and guidelines in allergology and allergen‐immunotherapy. SED has received consultation fees from AZ, GSK, Merck, Novartis, Regeneron, Sanofi, Teva; has participated in the speaker's bureaus of AZ, GSK, Sanofi. Other authors do not have any COI to declare.