Immunologically-mediated non-specific reactions
The most important group in this type of reactions is cross-intolerance to NSAIDs (CI) ,210,211 in which patients react to NSAIDs from different pharmacological groups related to its COX-1 inhibitory activity.191,210 CI has been classically divided into phenotypes with exclusive skin involvement (NSAIDs-exacerbated cutaneous disease (NECD) and NSAIDs-induced urticarial-angioedema (NIUA)) or with exclusive respiratory involvement (NSAIDs-exacerbated respiratory disease, NERD) .28Nevertheless, novel data indicate that almost 30% of patients with CI can experience blended reactions, especially involving skin and airways.212 Genetic predisposition might account for the burden of some CI phenotypes (e.g. variants of GNAI2 in NIUA) (Figure 7).213
As the underlying mechanism is related to arachidonic acid metabolism, potential biomarkers focus on determining leukotriene and prostaglandin metabolites. Therefore, urinary LTE4 has been reported as a useful biomarker to distinguish between different sub-phenotypes in NERD,214 between NERD and aspirin-tolerant asthma214 and phenotypes with skin involvement (NIUA and NECD) .215 Sensitivity and specificity of urinary LTE4 for identifying NERD has been reported to range from 0.55-0.81 and 0.77-0.82, respectively, which depends on the detection method used.216 Serum LTE4 and LTE4/PGF2 ratio have also been reported as potential in vitro biomarkers for NERD217 and urinary PGF2 for NIUA and NECD (Table 1).215