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.