NSAIDs 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 during asthma exacerbations together with intensified asthma treatment in children and adults.2Current 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.3-5 RV is responsible for up to 76% of exacerbations of wheeze in children and up to 83% of asthma attacks in adults.3-5 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 pathways8 (Fig. 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 RSV14 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.