AERD as an informative phenotypic variant
As many as 15% of patients with CRSwNP have comorbid asthma and an intolerance to inhibitors of cyclooxygenase 1 (COX-1)88,89. This clinical triad is commonly referred to as Aspirin Exacerbated Respiratory Disease (AERD) in North America. The acronym NERD (NSAID Exacerbated Respiratory Disease) is often used in Europe but has not been adopted in North America as the word has negative connotations. While there is overlap between the phenotypes (and endotypes) of AERD and CRSwNP, important distinctions exist. AERD is the most severe sub-phenotype of CRSwNP. AERD patients typically have more severe sinonasal inflammation, their polyps grow quickly, and they undergo more sinus surgeries due to the recalcitrant nature of their disease 89,90. Intolerance to COX-1 inhibitors has unique implications for clinical management of AERD. Aspirin desensitization followed by daily high-dose aspirin therapy can provide clinical benefit for patients with AERD but not for those with CRSwNP that tolerate COX-1 inhibitors 91,92. AERD is predominantly characterized by type 2 inflammation. Studies are conflicting as to whether type 2 cytokine levels in AERD are similar or increased compared to CRSwNP, but levels are significantly elevated versus healthy controls 77,93. In support of this, AERD patients clinically respond to type-2 biologics94,95 and, in some studies, even more so than patients with CRSwNP 96. As with observations in CRSwNP and CRSsNP, Type 1 and type 3 endotypes have recently been described in AERD93,97. A dysregulation of arachidonic acid metabolism uniquely distinguishes pathogenesis of AERD from CRSwNP. AERD patients have a characteristic over-production of cysteinyl leukotrienes and PGD2 but reduced levels of PGE298. AERD patients also have marked activation of the 15 Lipoxygenase pathway, now thought to be important in CRS.99,100 AERD patients with higher levels of urinary PGD2 may fail to tolerate an aspirin desensitization compared to patients with lower PGD2 levels, suggesting that sub-endotypes of AERD may also be present and clinically relevant101.