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).

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 E<sub>4</sub> and an underproduction of anti-inflammatory mediators such as prostaglandin E<sub>2</sub>. This imbalance, among other factors, leads to chronic inflammation of the respiratory tract.

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. 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

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 E<sub>2</sub> (PGE<sub>2</sub>) decreases inhibition of 5-lipoxygenase (5-LO), causing increased conversion of arachidonic acid into leukotriene A4 (LTA<sub>4</sub>). LTA<sub>4</sub> is converted into leukotriene C (LTC), which itself is converted into leukotriene D (LTD) and leukotriene E (LTE), both powerful bronchoconstrictors. In contrast to PGE<sub>2</sub>, AERD patients show significantly higher levels of prostaglandin D<sub>2</sub> (PGD<sub>2</sub>), which exerts pro-inflammatory effects via its recruitment of eosinophils and type 2 helper T cells (T<sub>H</sub>2) cells in addition to its direct bronchoconstrictive action.

alt=Flow diagram with arrows pointing from arachidonic acid to the eicosanoid products produced, including leukotrienes and prostaglandins|thumb|400x400px|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 PGD<sub>2</sub> and LTE levels, instead of the expected decrease in PGD<sub>2</sub> and relative lack of change in LTE. However, given that COX-1 catalyzes the formation of PGE<sub>2</sub>, a leading explanation is that patients have an increased dependence on PGE<sub>2</sub> and its corresponding receptor (EP2) to prevent inflammatory mediator release from mast cells. When COX-1 is inhibited, the decreased PGE<sub>2</sub> production leads to mast cell degranulation and release of LTC and PGD<sub>2</sub>, which leads to respiratory symptom exacerbation.

Patients with AERD also show increased expression of leukotriene C synthase (LTCS), which converts LTA<sub>4</sub> 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.

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. 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. 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.

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. 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&nbsp;mg to 1300&nbsp;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.

Risk of adverse advents such as bleeding or gastrointestinal side effects is relatively high with daily aspirin therapy. Even an 81&nbsp;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. Among treatment options, biologics have the highest certainty and magnitude of improvement effect. However, due to the high cost and systemic nature of biologics, some patients whose symptoms are sufficiently controlled with other treatments may prefer to avoid them or not qualify under stricter prescription guidelines. The mechanism through which dupilumab treats AERD and restores aspirin tolerance is not fully understood, but it is theorized that by blocking IL-4α, dupilumab increases expression of EP2, the receptor for PGE<sub>2</sub>, back to normal levels, normalizing COX function and PGE<sub>2</sub> production. Low PGE<sub>2</sub> production and activity appear to play a key role in AERD, as PGE<sub>2</sub> prevents inflammatory mediator release from mast cells and inhibits 5-LO function, which decreases production of CysLTs.

Antileukotrienes

Leukotrienes are a family of inflammatory mediators derived from arachidonic acid that include CysLTs implicated in AERD pathophysiology. Drugs that prevent leukotriene production, such as zileuton, and that block leukotriene receptors, such as montelukast and zafirlukast, have proven to be useful in treatment of nasal polyposis. However, there may be limited additional benefit when used in conjunction with intra-nasal corticosteroids. In a large survey, AERD patients reported that zileuton was more effective at controlling their symptoms than montelukast. Despite this, zileuton remains less prescribed than montelukast, likely due to concerns around risk of liver enzyme elevation.

Surgery

Often functional endoscopic sinus surgery is required to remove nasal polyps, although they typically recur, particularly if aspirin desensitization is not undertaken. Approximately, 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 down-regulated, hinting at the de-differentiation phenomenon in AERD polyps.

Diet

Low omega-6/high omega-3

Given that dysregulation of the arachidonic acid cascade has been implicated in AERD pathogenesis and that production of arachidonic acid and its downstream products is influenced by the interaction and metabolism of omega-3 and omega-6 essential fatty acids, dietary interventions targeting the two essential fatty acids are under study.

A diet low in omega-6 fatty acids and high in omega-3 fatty acids—the opposite of an average modern western diet—has been shown to reduce arachidonic acid precursors and increase eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA and DHA are precursors for anti-inflammatory compounds that modulate leukotrienes, prostaglandins and thromboxanes that have been implicated in AERD pathogenesis. Initial studies have shown that decreasing omega-6 intake and increasing omega-3 intake decrease urinary LTE and prostaglandin D levels and significantly improved overall symptoms. AERD specialists routinely recommend this diet as a treatment option. 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.

Dietary salicylates

Given that aspirin is a salicylate, specifically acetyl salicylic acid, research has gone into low-salicylate diets such as the Feingold diet to see if they benefit AERD patients. For example, 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.

  • Aspirin-induced asthma
  • Aspirin-intolerant asthma
  • NSAID-exacerbated respiratory disease (NERD)
  • Samter's triad (named for Max Samter)
  • Leukotriene associated hypersensitivity
  • Acetylsalicylic acid triad
  • Widal's triad (named for Georges-Fernand Widal)
  • Francis' triad
  • Aspirin triad
  • Aspirin-induced asthma and rhinitis (AIAR)

History

The first adverse reactions to aspirin were described in 1902 in Germany, only four years after aspirin's commercial introduction. The first published report of an aspirin-induced asthma attack was in 1911. Initial reports on the linkage between asthma, aspirin, and nasal polyposis were made by Georges-Fernand Widal et al. in 1922. Further studies were conducted by Samter and Beers in reports published in 1968, which brought full clinical characterization. The recognition Samter brought to the disease through his studies led to it being called "Samter's triad", although today "aspirin-exacerbated respiratory disease" is preferred to better reflect the progressive nature of the condition even when patients abstain from NSAIDs.

See also

  • Salicylate sensitivity
  • Drug intolerance
  • Alcohol-induced respiratory reactions

References

ja:アスピリン喘息