Aspirin-exacerbated respiratory disease (AERD), also called NSAID-exacerbated respiratory disease (N-ERD) or historically aspirin-induced asthma and Samter's triad, is a long-term disease defined by three simultaneous symptoms: asthma, chronic rhinosinusitis with nasal polyps, and intolerance of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). Compared to aspirin tolerant patients, AERD patients' asthma and nasal polyps are generally more severe. Reduction or loss of the ability to smell is extremely common, occurring in more than 90% of people with the disease. AERD most commonly begins in early- to mid-adulthood and has no known cure. While NSAID intolerance is a defining feature of AERD, avoidance of NSAIDs does not affect the onset, development or perennial nature of the disease.
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 currently unknown. This dysregulation leads to an imbalance of immune related molecules, including an overproduction of inflammatory compounds such as leukotriene E4 and an underproduction of anti-inflammatory mediators such as prostaglandin E2. This imbalance, among other factors, leads to chronic inflammation of the respiratory tract.
A history of respiratory reactions to aspirin or others NSAIDs is sufficient to diagnose AERD in a patient that has both asthma and nasal polyps. However, diagnosis can be challenging during disease onset, as symptoms do not usually begin all at once. As symptoms appear, AERD may be misdiagnosed as simple allergic or nonallergic rhinitis or adult-onset asthma alone. It is only once the triad of symptoms are present that the diagnosis of AERD can be made.
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 patient's 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. In addition, there is no relationship between past use of NSAIDs and onset of AERD
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 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 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 E (uLTE) concentration is also a sign of AERD, especially when noted in conjunction with the criteria listed above due. High uLTE concentration alone cannot be used to diagnose AERD, however it may be possible to rule out AERD in patients without high uLTE due to its strong negative predictive value. Urinary LTE 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