aspirin-exacerbated respiratory disease aspirin-exacerbated respiratory disease aspirin-exacerbated respiratory disease (aerd), also called nsaid-exacerbated respiratory disease (nerd/n-erd) or historically aspirin-induced asthma and samter's triad, refers to the triad of asthma, chronic rhinosinusitis with nasal polyps, and intolerance of aspirin and other nonsteroidal anti-inflammatory drugs (nsaids). aerd most commonly begins in early- to mid-adulthood and is a chronic disease that has no known cure. the cause of the disease is a dysregulation of the arachidonic acid metabolic pathway and of various innate immune cells, though the initial cause of this dysregulation is not currently know. while nsaid intolerance is a defining feature of aerd, simple avoidance does not prevent the onset, development or perennial nature of the disease. aspirin-exacerbated respiratory diseaseother namesaspirin-induced asthma, samter's triad, samter's syndrome, nonsteroidal anti-inflammatory drug (nsaid)-exacerbated respiratory disease (nerd/n-erd)coated aspirin tabletsspecialtyrhinology, pulmonology, allergologysymptomsadult-onset asthma, chronic rhinosinusitis with nasal polyps, nsaid hypersensitivity reactionsusual onset20s to 40s, average age 35-36durationlong termcauseschronic immune dysregulation of unknown origindiagnostic methodsymptoms and medical history; aspirin challengedifferential diagnosisallergic rhinitis, nonallergic rhinitis, nonallergic rhinitis with eosinophilia syndrome (nares)managementinhaled and intranasal corticosteroids, aspirin desensitization and therapy, biologics, sinus surgery, diet, antileukotrienesfrequency0.3–0.9% (general population, us), ~7% of asthmatics as there is no cure, treatment of aerd revolves around managing the symptoms of the disease. corticosteroids, surgery, diet modifications and monoclonal antibody-based drugs are all commonly used, among other treatment options. paradoxically, daily aspirin therapy after an initial desensitization can also help manage symptoms. reactions to aspirin and other nsaids range in severity but almost always have a respiratory component; severe reactions can be life threatening. the symptoms of nsaid-induced reactions are hypersensitivity reactions rather than allergic reactions that trigger other allergen-induced asthma, rhinitis, or hives. aerd is not considered an autoimmune disease, but rather a chronic immune dysregulation. eaaci/who classifies the syndrome as one of five types of nsaid hypersensitivity. signs and symptoms aerd affects an estimated 0.3–0.9% of the general population in the us, including around 7% of all asthmatics, about 14% of adults with severe asthma, and ~5-10% of patients with adult onset asthma. aerd is uncommon among children, with around 6% of patients, predominantly female, reporting disease onset during childhood. it is more prevalent among women by up to a 2:1 margin, usually begins in the patients twenties to forties, with mean age of onset around 35. aerd patients may not have any allergies, though allergies are significantly more common in aerd patients than the general population. while aerd has been found to affect essentially all ethnicities, it is less common in parts of asia where nasal polyps caused by type 2 inflammation are relatively more rare. while disease progression varies, most commonly the first symptom is rhinitis (inflammation or irritation of the nasal mucosa), which may manifest as sneezing, runny nose, or congestion. the disorder typically progresses to asthma, then nasal polyposis, with aspirin sensitivity coming last. hyposmia or anosmia—reduction or loss of the ability to smell—are reported in more than 90% of patients, as inflammation within the nose and sinuses likely reaches the olfactory receptors. reactions to nsaids range in severity and expression. onset is usually relatively rapid, with a mean time of around one hour after ingestion, though reactions as late as three hours have been reported. respiratory reactions are essentially universal, with bronchoconstriction occurring in close to 90% of patients and nasal congestion and rhinorrhea occurring in more than 40%. other symptoms include urticaria (hives), flushing, angioedema and hypotension. gastrointestinal reactions have also been reported in a subset of patients, and may be difficult to treat. factors that affect reaction severity include nsaid dosage, underlying asthma control, leukotriene modifier usage and the state of the patient's nasal polyps. in addition to aspirin, patients also react 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. causes and pathophysiology 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. 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 c4 (ltc4), which itself is converted into leukotriene d4 (ltd4) and leukotriene e4 (lte4), 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. simplified overview of the arachidonic acid metabolic cascade and some of its relevant downstream products 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 lte4 levels, instead of the expected decrease in pgd2 and relative lack of change in lte4. 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 release from mast cells. when cox-1 is inhibited, the decreased pge2 production leads to mast cell degranulation and release of ltc4 and pgd2, which leads to respiratory symptom exacerbation. patients with aerd also show increased expression of leukotriene c4 synthase (ltc4s), which converts lta4 into ltc4. platelets, which express ltc4s and generate ltc4 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. an overview of some of the immune cells and molecules involved in the negative cycle of disease 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 degranulated in aerd nasal polyps, also appear to be important sources of il-4 and il-13. in addition to activating 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 allergies, common asthma, and/or nonallergic rhinitis. aerd is generally diagnosed based on a patient's medical history, however an oral aspirin challenge at a specialized facility is considered the most definitive method of diagnosis. patients are considered candidates for an aerd diagnosis if they meet the following three points: history of adverse reactions to aspirin or other nsaids reduced ability to smell (hyposmia or anosmia) history of rhinosinusitis and nasal polyps further, if a patient meets two or more of the following criteria, then an aerd diagnosis is strongly considered: moderate or severe asthma asthma with an intractable cough onset of asthma after adolescence a weakly atopic disposition 10% or greater increase in peripheral eosinophilia high urinary leukotriene e4 (ulte4) concentration is also a sign of aerd, especially when noted in conjunction with the criteria listed above due. high ulte4 concentration alone cannot be used to diagnose aerd, however it may be possible to rule out aerd in patients without high ulte4 due to its strong negative predictive value. urinary lte4 concentration is generally around 3 to 5 times higher in patients with aerd that it is in those with aspirin-tolerant asthma, and increases 2 to 30 fold during an aspirin challenge test. management medication since nasal polyps have been identified as an important source of inflammatory compounds in aerd, much effort goes into the prevention of polyp growth and control of sinus symptoms in general. there is evidence supporting four different long-term pharmacological treatments to this end: intra-nasal corticosteroids, aspirin desensitization and therapy, a range of biologic medicines, and antileukotrienes. each treatment has benefits and drawbacks, so no one option can be recommended for all patients. asthma symptoms, if not controlled via biologics or other means, are managed with standard asthma treatments such as inhaled corticosteroids and long-acting beta-agonists. despite optimal medical management, many patients continue to require oral steroid medications to alleviate asthma and chronic nasal congestion. intra-nasal corticosteroids common corticosteroids such as fluticasone or budesonide are often used as a first line treatment for aerd. they can be delivered topically to the nasal and sinus mucosa via a variety of methods, such as nasal spray, rinse, drops, stents and exhalation delivery systems. overall effectiveness is low-to-moderate, but wide availability and low cost make this a widely used treatment option. stent, spray and exhalation delivery systems are generally among the most beneficial depending on outcome measured, while no major differences in adverse effects have been measured between delivery methods. aspirin desensitization and therapy avoidance of nsaid medications will not stop the progression of the disease. however, one treatment option is desensitization to aspirin, undertaken at a clinic or hospital specializing in such treatment. patients who are desensitized then take a maintenance dose of aspirin daily to maintain their desensitization. the recommended maintenance dose for symptom control is 650 mg to 1300 mg aspirin daily. while on daily aspirin, patients experience improved quality of life and reduced nasal symptoms, however, there is no improvement in smell compared to placebo and there is no reduction in the need for oral corticosteroids or rescue surgery. once desensitized to aspirin, most patients can safely take other nsaid medications again as long the daily maintenance dose is continued. risk of adverse advents such as bleeding or gastrointestinal side effects is relatively high with daily aspirin therapy. even a 81 mg daily aspirin regimen for cardiovascular benefits has been shown to increase risk of long-term bleeding, so the significantly higher aspirin doses used for maintenance therapy are of some concern. this is borne out in studies on aerd patients—compared against standard of care and