Causal concept of NSAID-triggered eicosanoid imbalance for in vitro diagnosis of AERD. The causal concept of NSAID-trigger eicosanoid imbalance for in vitro diagnosis of AERD is best allegorised as a tray balancing all parameters (which might be relevant for the pathway) on a needle. Disease-free individuals: housekeeping PGE₂ balances synthesis of pLT (e.g., by induction of endogenous cAMP, which inhibits synthesis of pLT); expression of enzymes or receptors are unremarkable (A1). Upon exposure to NSAIDs the PGE₂ level is diminished but remains high enough ensuring “uncritical” levels of pLT (even though cAMP might by diminished); expression of enzymes and/or receptors are not modified (A2). Patients with AERD: synthesis of housekeeping PGE₂ is diminished, but still balances synthesis of pLT (e.g., by reduced endogenous cAMP); expression of enzymes (up regulation of LTC₄-synthase) or receptors (up regulation of cysLT) can be mutated in some cases (B1). Exposure to NSAIDs/aspirin blocks the COX-pathway causing reduced synthesis of PGE₂ (and consequently further reduced cAMP level), and consequently the metabolism of arachidonic acid is shifted to the 5LO-pathway provoking elevated synthesis of pLT; expression of enzymes and/or receptors may by altered, but not modified by NSAIDs (B2).