to other NSAIDs such as ibuprofen, and to any medication that inhibits the cyclooxygenase-1 (COX-1) enzyme, although paracetamol (acetaminophen) in low doses is generally considered safe. Selective COX-2 inhibitor NSAIDs that do not block COX-1, such as the celecoxib and rofecoxib, also are regarded as safe. Nonetheless, recent studies do find that these types of drugs, e.g. acetaminophen and celecoxib, may trigger adverse reactions in these patients; caution is recommended in using any COX inhibitors. In addition to aspirin and NSAIDs, consumption of even small amounts of alcohol also produces uncomfortable respiratory reactions in many patients. Cause The reason for onset of AERD is currently unknown. Allergic reaction to the superantigen of Staphylococcus aureus, chronic viral infection and autoimmune mechanisms have been theorized, among others, though there is not sufficient evidence to support any specific theory. No strong genetic predisposition to or basis of AERD has been found, and familial AERD is rare. Pathophysiology AERD is generally thought to have two major components contributing to disease pathogenesis: abnormalities in the arachidonic acid metabolic cascade and dysregulation of various innate immune cells. These two components feed into each other in a highly complex negative cycle of increasing inflammation and dysregulation that is still under active research. Arachidonic acid cascade dysregulation AERD is associated with an aberrant arachidonic acid metabolism that leads to changes in levels of two major classes of eicosanoids, specifically certain cysteinyl leukotrienes (cysLTs) and prostaglandins. Notably, reduced prostaglandin E2 (PGE2) decreases inhibition of 5-lipoxygenase (5-LO), causing increased conversion of arachidonic acid into leukotriene A4 (LTA4). LTA4 is converted into leukotriene C (LTC), which itself is converted into leukotriene D (LTD) and leukotriene E (LTE), both powerful bronchoconstrictors. In contrast to PGE2, AERD patients show significantly higher levels of prostaglandin D2 (PGD2), which exerts pro-inflammatory effects via its recruitment of eosinophils and type 2 helper T cells (TH2) cells in addition to its direct bronchoconstrictive action. The exact mechanism by which aspirin and other COX-1 inhibitors lead to acute respiratory reactions is still under investigation. AERD patients exhibit a seemingly paradoxical response to COX-1 inhibition, as it leads to greatly increased PGD2 and LTE levels, instead of the expected decrease in PGD2 and relative lack of change in LTE. However, given that COX-1 catalyzes the formation of PGE2, a leading explanation is that patients have an increased dependence on PGE2 and its corresponding receptor (EP2) to prevent inflammatory mediator