Aspirin exacerbated respiratory disease
Aspirin exacerbated respiratory disease (AERD),  also termed aspirin-induced asthma, is a medical condition initially defined as consisting of three key features: asthma, respiratory symptoms exacerbated by aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), and nasal polyps. The symptoms of respiratory reactions in this syndrome are hypersensitivity reactions to NSAIDs rather than the typically described true allergic reactions that trigger other common allergen-induced asthma, rhinitis, or hives. The NSAID-induced reactions do not appear to involve the common mediators of true allergic reactions, immunoglobulin E or T cells. Rather, AERD is a type of NSAID-induced hypersensitivity syndrome. EAACI/WHO classifies the syndrome as one of five types of NSAID hypersensitivity or NSAID hypersensitivity reactions.

Signs and symptoms
The various non-allergic NSAID hypersensitivity syndromes affect 0.5–1.9% of the general population, with AERD affecting about 7% of all asthmatics and about 14% of adults with severe asthma. AERD, which is slightly more prevalent in women, usually begins in young adulthood (twenties and thirties are the most common onset times, although children are affected by it and present a diagnostic problem in pediatrics) and may not include any other allergies. 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. Anosmia (lack of smell) also is common, as inflammation within the nose and sinuses likely reaches the olfactory receptors.The respiratory reactions to NSAIDs vary in severity, ranging from mild nasal congestion and eye watering to lower respiratory symptoms including wheezing, coughing, an asthma attack, and in rare cases, anaphylaxis. In addition to the typical respiratory reactions, about 10% of patients with AERD manifest skin symptoms such as urticaria and/or gastrointestinal symptoms such as abdominal pain or vomiting during their reactions to aspirin.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. NSAIDs that are highly selective in blocking COX-2 and do not block its closely related paralog, COX-1, such as the COX-2 inhibitors 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 disorder is thought to be caused by an anomaly in the arachidonic acid metabolizing cascade that leads to increased production of pro-inflammatory cysteinyl leukotrienes, a series of chemicals involved in the bodys inflammatory response. When medications such as NSAIDs or aspirin block the COX-1 enzyme, production of thromboxane and some anti-inflammatory prostaglandins is decreased, and in patients with aspirin-induced asthma, this results in the overproduction of pro-inflammatory leukotrienes, which can cause severe exacerbations of asthma and allergy-like symptoms. The underlying cause of the disorder is not fully understood, but there have been several important findings:

Abnormally low levels of prostaglandin E2 (PGE2), which is protective for the lungs, has been found in patients with aspirin-induced asthma and may worsen their lung inflammation.
In addition to the overproduction of cystinyl leukotrienes, overproduction of 15-lipoxygenase-derived arachidonic acid metabolites viz., 15-hydroxyicosatetraenoic acid and eoxins by the eosinophils isolated from the blood of individuals with AERD; certain of these products may help promote the inflammatory response.
Overexpression of both the cysteinyl leukotriene receptor 1 and the leukotriene C4 synthase enzyme has been shown in respiratory tissue from patients with aspirin-induced asthma, which likely relates to the increased response to leukotrienes and increased production of leukotrienes seen in the disorder.
The attachment of platelets to certain leukocytes in the blood of patients with aspirin-sensitive asthma also has been shown to contribute to the overproduction of leukotrienes.
There may be a relationship between aspirin-induced asthma and TBX21, PTGER2, and LTC4S.
Eosinophils isolated from the blood of aspirin-induced asthma subjects (as well as severe asthmatic patients) greatly overproduce 15-hydroxyicosatetraenoic acid and eoxin C4 when challenged with arachidonic acid or calcium ionophore A23187, compared to the eosinophils taken from normal or mildly asthmatic subjects; aspirin treatment of eosinophils from aspirin intolerant subjects causes the cells to mount a further increase in eoxin production. These results suggest that 15-lipoxygenase and certain of its metabolites, perhaps eoxin C4, is contributing to aspirin-induced asthma in a fashion similar to 5-lipoxygenase and its leukotriene metabolites.

Treatment
Medication
Avoidance of NSAID medications will not stop the progression of the disease. The preferred treatment for many patients 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, most patients have reduced need for supporting medications, fewer asthma and sinusitis symptoms than previously, and an improved sense of smell. Desensitization to aspirin reduces the chance of nasal polyp recurrence and may slow the regrowth of nasal polyps. Once desensitized to aspirin, most patients can safely take other NSAID medications again.Even patients desensitized to aspirin may continue to need other medications including nasal steroids, inhaled steroids, and leukotriene antagonists. Leukotriene antagonists and inhibitors (montelukast, zafirlukast, and zileuton) often are helpful in treating the symptoms of AERD. In a large survey of AERD patients, it was reported that Zyflo (zileuton) was significantly more effective at controlling the symptoms of the disease than Singulair (montelukast).Biologic medications such as dupilumab, mepolizumab, and omalizumab may also be of benefit. In a 2021 survey of biologics, dupilumab was found to be most effective in treating symptoms of AERD.Despite optimal medical management, many patients continue to require oral steroid medications to alleviate asthma and chronic nasal congestion.

Surgery
Often surgery is required to remove nasal polyps, although they typically recur, particularly if aspirin desensitization is not undertaken. 90% of patients have been shown to have recurrence of nasal polyps within five years after surgery, with 47% requiring revision surgery in the same time period. A complete endoscopic sinus surgery followed by aspirin desensitization has been shown to reduce the need for revision surgeries. Exact cause of nasal polyp formation is unknown. However, Differential gene expression analysis of AERD nasal polyp epithelial cells versus AERD non polyp nasal mucosa revealed DMRT3 could be potentially involved in nasal polyp development in AERD patients. Furthermore, several genes are downregulated, hinting at the dedifferentiation phenomenon in AERD polyps.

Diet
The majority of those with aspirin exacerbated respiratory disease experience respiratory reactions to alcohol. One study found that 83% reported such reactions. Of those who had reactions, 75% had a sinus reaction (runny nose, nasal congestion) and 51% had a lower respiratory reaction (wheezing, shortness of breath). The current theory on the cause of these reactions is that they may be related to polyphenols found in alcoholic beverages. A 2017 study found that alcohol sensitive patients reacted to catechins in red wine, but not to resveratrol. It has been suggested that steel fermented white wines and clear liquors may cause less of a reaction than other alcoholic beverages. Desensitization to aspirin has been found to reduce reactions to alcohol.Some people have reported relief of symptoms by following a low-salicylate diet such as the Feingold diet. Aspirin is quickly converted in the body to salicylic acid, also known as 2-Hydroxybenzoic acid. A prospective randomized trial with 30 patients following a low-salicylate diet for six weeks demonstrated a clinically significant decrease in both subjective and objective scoring of severity of disease, but made note of the challenge for patients in following what is a fairly stringent diet. Despite these findings, experts on the disease do not believe that dietary salicylates contribute to AERD symptoms. Dietary salicylates do not significantly inhibit the COX-1 enzyme, which is the cause of AERD reactions. One confounding factor in the study that showed a benefit from avoidance of dietary salicylates is that a low salicylate diet involves eliminating wine and beer. The majority of AERD patients react to wine and beer for reasons that do not involve their salicylate content. There is also a strong placebo effect involved with any dietary intervention. In contrast to aspirin, dietary salicylates are not acetylated and therefore do not block cyclooxygenases and hence, there is no rationale why a low salicylate diet would be beneficial for AERD patients.A diet low in omega-6 oils (precursors of arachidonic acid), and high in omega-3 oils may also be of benefit. In a small study, aspirin-sensitive asthma patients taking 10 grams of fish oil daily reported relief of most symptoms after six weeks, however, symptoms returned if the supplement was stopped. In another study, a diet low in omega 6 fatty acids and high in omega 3 fatty acids significantly reduced sinus symptoms in AERD patients.

Alternate and related names
Aspirin-induced asthma
Leukotriene associated hypersensitivity 
Samters triad
Acetylsalicylic acid triad 
Widals triad
Francis triad
Aspirin triad
Aspirin-exacerbated respiratory disease (AERD).
NSAID-exacerbated respiratory disease (NERD)
Aspirin-induced asthma and rhinitis (AIAR) A person who has not yet experienced asthma or aspirin sensitivity might be diagnosed as having:

Non-allergic rhinitis
Non-allergic rhinitis with eosinophilia syndrome (NARES)

History
The syndrome is named for Max Samter.Initial reports on a linkage among asthma, aspirin, and nasal polyposis were made by Widal in 1922. Further studies were conducted by Samter and Beers in reports published in 1968.

See also
Salicylate sensitivity
Drug intolerance
Alcohol-induced respiratory reactions

References


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