NSAID-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 LTE4.173,174 Some patients have higher excretion of LTE4 also during a stable period of NERD.74,175-177 It is debatable, which cells produce cysteinyl-LTs in NERD. Since overproduction of PGD2 and increase of histamine concentration accompanies 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 EP2expression were observed.174,178 When PGE2 is further decreased, it leads to mast cell activation and bronchoconstriction because it removes the stabilising effect of PGE2 on mast cell mediator release131. Accordingly, inhalation of PGE2 before aspirin challenge prevented reduction in pulmonary function and mast cell activation.179However, 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.180 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).181,182 Highly selective inhibitors of COX-2 like coxibs (e.g. celecoxib, etoricoxib)183are well tolerated in most NERD patients, whereas preferential COX-2 inhibitors (nimesulide, meloxicam) can trigger symptoms at high doses184 (Table 1) . Diclophenac, ketorolac, ibuprofen, naproxen, indomethacin or pyrazolone derivatives inhibits both COX-2 and COX-1,185 therefore are contraindicated in NERD. Acetylsalicylic acid is more potent inhibitor of COX-1 than COX-2.183,186 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