release from mast cells. When COX-1 is inhibited, the decreased PGE2 production leads to mast cell degranulation and release of LTC and PGD2, which leads to respiratory symptom exacerbation. Patients with AERD also show increased expression of leukotriene C synthase (LTCS), which converts LTA4 into LTC. Platelets, which express LTCS and generate LTC when attached to 5-LO-expressing leukocytes (including eosinophils), are also implicated in disease pathogenesis as well as acute aspirin-induced exacerbations. Additionally, after aspirin or other NSAID exposure, AERD patients generally become desensitized and tolerate a second exposure for around one week, which lines up with the half life of circulating platelets. Additional downstream products of arachidonic acid such as 15-lipoxygenase (15-LO) produced 15-HETE and 15-Oxo-ETE are significantly elevated in nasal polyps from AERD patients while other products like anti-inflammatory lipoxins are reduced. It's possible that increased 15-LO activity and preferential conversion of arachidonic acid into 15-Oxo-ETE and eoxins over lipoxins contributes to inflammation in AERD. Innate immune cells Various innate immune cells also appear to play important roles in AERD pathogenesis. Eosinophils, mast cells, basophils and type 2 innate lymphoid (ILC2) cells have all been found at increased levels in the nasal polyps of AERD patients and appear to be part of the negative cycle of inflammation in AERD. ILC2 cells are activated by CysLTs and PGD2 in addition to a class of cytokines called alarmins that are released by epithelial cells, including IL-25, IL-33 and thymic stromal lymphopoietin (TSLP). Strongly activated ILC2s release IL-4, IL-5 and IL-13. These cytokines lead to increased eosinophil recruitment, excessive mucus production via goblet cells, and promotion of TH2 and immunoglobulin E responses. These responses cause the epithelial cells to release more cytokines and inflammatory molecules, creating a feed-forward negative cycle of increasing inflammation. Eosinophils are also activated by ILC2-released IL-5 and epithelial-cell released IL-33, causing them to release more CysLTs and PGD2, which in turn further active ILC2. Likewise, mast cells are also activated by epithelial-cell released IL-25, IL-33 and TSLP, leading to further CysLT and PGD2 production. Basophils, which are extensively degranulated in AERD nasal polyps, also appear to be important sources of IL-4 and IL-13. In addition to activiating immune cells, IL-4 and IL-13 have been shown to significantly increase 15-LO activity, further playing into the cycle of dysregulation and disease. Diagnosis Diagnosis of AERD can be difficult, as symptoms develop over time and can often be attributed to