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Salicylate sensitivity

Salicylate sensitivity, also known as salicylate intolerance, is a non-immunological adverse reaction to salicylates—naturally occurring chemicals found in many fruits, vegetables, spices, and herbs, as well as synthetic compounds in medications like aspirin—characterized by pseudo-allergic hypersensitivity responses rather than true IgE-mediated allergies.^[1]^[2] This condition arises from the inhibition of cyclooxygenase enzymes, leading to disrupted eicosanoid metabolism and the overproduction of pro-inflammatory leukotrienes, which triggers symptoms in susceptible individuals.^[1] It is estimated to affect 0.3–2.5% of the general population, with prevalence up to 7–20% among adults with asthma (as of the 2020s).^[1]^[3]^[4] Symptoms primarily affect the respiratory, dermatological, and gastrointestinal systems and often overlap with aspirin-exacerbated respiratory disease (AERD), or Samter's triad (asthma, nasal polyps, and aspirin sensitivity).^[1]^[5] Diagnosis involves clinical history and provocation tests, while management emphasizes avoidance of salicylates, though dietary interventions have limited and debated efficacy; for AERD, aspirin desensitization is a key therapy.^[1]^[2]^[6]

Definition and Terminology

Definition

Salicylate sensitivity, also referred to as salicylate intolerance, is defined as a non-immunological adverse reaction to normal therapeutic or dietary amounts of salicylates, resulting in symptoms such as respiratory, cutaneous, or gastrointestinal disturbances.^[1] Unlike true allergies, which involve IgE-mediated immune responses, salicylate sensitivity operates through pseudo-allergic or pharmacological pathways, often linked to altered arachidonic acid metabolism.^[1] It is also distinct from salicylism, the acute toxicity syndrome caused by excessive doses of salicylates like aspirin, which affects individuals regardless of predisposition and leads to severe systemic effects such as tinnitus, hyperventilation, and metabolic acidosis.^[1] Salicylates are chemical compounds derived from salicylic acid, a naturally occurring phenolic substance found in various plants, including the bark of willow trees (Salix species), where it serves as a defense mechanism against pathogens.^[7] In modern contexts, salicylates appear in high concentrations in everyday foods such as fruits (e.g., berries, apples), vegetables (e.g., broccoli, tomatoes), spices (e.g., curry, paprika), and herbs, as well as in synthetic forms within medications (e.g., aspirin and other nonsteroidal anti-inflammatory drugs), food preservatives, and personal care products like perfumes and acne treatments.^[1]^[8] This sensitivity typically manifests as a pseudo-allergic response, where exposure triggers the release of inflammatory mediators like leukotrienes due to inhibition of cyclooxygenase enzymes, mimicking allergic symptoms without involving antigen-specific immunity.^[1]

Terminology and Classification

Salicylate sensitivity, also referred to interchangeably as salicylate intolerance or aspirin sensitivity, describes a non-immunological adverse reaction to salicylates, compounds found in certain medications like aspirin and in various foods.^[1] This condition is distinct from aspirin allergy, which involves IgE-mediated immunological mechanisms, and from salicylism, a form of toxicity resulting from acute overdose of salicylates leading to symptoms such as tinnitus, hyperventilation, and metabolic acidosis.^[9] Instead, salicylate sensitivity arises from pharmacological effects, primarily the inhibition of cyclooxygenase-1 (COX-1) enzymes, disrupting arachidonic acid metabolism and eicosanoid balance without immune system involvement.^[1] The classification of salicylate sensitivity encompasses several subtypes based on predominant clinical manifestations, often cross-reactive with other nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit COX-1. One major subtype is aspirin-exacerbated respiratory disease (AERD), characterized by the triad of asthma, chronic rhinosinusitis with nasal polyps, and hypersensitivity to aspirin or other COX-1 inhibitors, also known as Samter's triad.^[9] Another subtype involves cutaneous reactions, such as urticaria or angioedema, where exposure triggers hive-like rashes or swelling through increased leukotriene production.^[1] A third subtype manifests as gastrointestinal intolerance, featuring symptoms like diarrhea or chronic inflammation due to altered prostaglandin synthesis in the gut.^[1] Historically, the terminology for these reactions evolved from early descriptions as "pseudo-allergy" or "pseudoimmunopathy" in the mid-20th century, reflecting their mimicry of allergic responses without immunological basis, to more precise terms like "pharmacological intolerance" by the late 20th century, emphasizing the drug's direct biochemical effects.^[1] This shift, prominent by the 1970s in medical literature, aligned with growing understanding of COX inhibition pathways and distinguished these reactions from true hypersensitivities.^[9] Salicylate sensitivity falls within the broader category of non-allergic hypersensitivity reactions, where pharmacological or metabolic disruptions cause symptoms resembling allergies, and it overlaps with food intolerances, as dietary salicylates from sources like fruits and spices can provoke similar responses through the same eicosanoid imbalances.^[1]

Pathophysiology and Etiology

Pathophysiological Mechanisms

Salicylate sensitivity primarily arises from the inhibition of cyclooxygenase (COX-1 and COX-2) enzymes by salicylates, such as aspirin, which disrupts the arachidonic acid metabolic pathway. This inhibition reduces the synthesis of protective prostaglandins, particularly prostaglandin E2 (PGE2), leading to a metabolic shunt of arachidonic acid toward the 5-lipoxygenase (5-LO) pathway and subsequent overproduction of cysteinyl leukotrienes (CysLTs).^[10]^[1] The elevated CysLTs, including leukotriene C4 (LTC4) and D4 (LTD4), play a central role in the inflammatory response characteristic of salicylate sensitivity, particularly in aspirin-exacerbated respiratory disease (AERD). These mediators promote bronchoconstriction, vascular permeability, and mucosal edema by binding to CysLT1 and CysLT2 receptors on airway smooth muscle cells, eosinophils, and mast cells.^[10]^[11] In sensitive individuals, baseline overproduction of CysLTs is further amplified by salicylate exposure, exacerbating inflammatory cascades.^[1] Mast cell activation contributes significantly to the pseudo-allergic response in salicylate sensitivity, occurring independently of IgE-mediated mechanisms. Salicylates trigger the release of histamine, tryptase, and additional CysLTs from mast cells and basophils, amplifying inflammation without involving classical allergic pathways.^[10]^[1] Genetic factors, such as polymorphisms in leukotriene pathway genes including LTC4S (−444A>C), ALOX5, and CYSLTR1/CYSLTR2, predispose individuals to heightened CysLT production and receptor sensitivity, influencing disease susceptibility.^[11] Differences in salicylate metabolism underlie the accumulation of these compounds in sensitive individuals, leading to prolonged exposure and intensified pseudo-allergic reactions. Impaired detoxification pathways result in altered eicosanoid profiles, with elevated levels of pro-inflammatory metabolites like 15-hydroxyeicosatetraenoic acid (15-HETE) and eoxins, compared to non-sensitive populations.^[10]^[1] This metabolic dysregulation sustains the inflammatory imbalance triggered by COX inhibition.^[11]

Causes and Risk Factors

Salicylate sensitivity arises from a combination of genetic predispositions and environmental exposures that impair the body's ability to tolerate salicylates, compounds found in certain medications and foods. Genetic factors play a significant role, with variants in genes involved in arachidonic acid metabolism, such as polymorphisms in the 5-lipoxygenase gene (ALOX5) and leukotriene C4 synthase gene (LTC4S), increasing susceptibility to salicylate-induced reactions, particularly in aspirin-exacerbated respiratory disease (AERD).^[12] Additionally, variants in the filaggrin gene (FLG), which affects epithelial barrier integrity, have been identified in approximately 5% of AERD patients, contributing to heightened sensitivity through compromised skin and mucosal barriers.^[13] Other genetic associations include polymorphisms in HLA-DPB1, which may influence immune responses to salicylates.^[14] Environmental exposures represent primary non-genetic causes, primarily through ingestion of salicylates from dietary sources like fruits, vegetables, spices, and teas, as well as medications such as aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs).^[1] Cumulative exposure from diets rich in salicylate-containing plant-based foods—such as currants (up to 66 mg/kg) or curry (up to 2 mg/g)—can exacerbate sensitivity in predisposed individuals by overwhelming metabolic pathways.^[1] Key risk factors include coexisting atopic and inflammatory conditions that amplify salicylate intolerance. AERD, a subtype of salicylate sensitivity, occurs in 2-25% of asthmatic adults, with higher rates (up to 9%) in those with severe asthma.^[15] It is strongly linked to chronic rhinosinusitis with nasal polyps, where nearly all AERD cases feature this comorbidity, driven by shared eosinophilic inflammation.^[16] Atopic dermatitis increases risk, with meta-analyses indicating salicylate intolerance in up to 53% of affected individuals (95% CI 44-62%).^[17] Inflammatory bowel disease (IBD) patients face elevated risks due to intolerance to aminosalicylate therapies like mesalamine, which can worsen disease control and necessitate alternative treatments.^[18] Frequent NSAID use heightens risk by mimicking salicylate effects on arachidonic acid pathways. Non-genetic triggers such as infectious agents can precipitate sensitivity in at-risk individuals by temporarily disrupting immune homeostasis.^[1]

Clinical Presentation

Symptoms and Signs

Salicylate sensitivity manifests through a range of observable symptoms primarily affecting the respiratory, dermatological, and gastrointestinal systems, with additional effects possible in other areas. These signs typically arise following exposure to salicylates in foods, medications, or environmental sources, and their severity can vary among individuals.^[19]^[1] Respiratory symptoms are among the most common, particularly in individuals with aspirin-exacerbated respiratory disease (AERD), where they form a core component of the condition. These include nasal congestion, rhinitis, sinusitis, sneezing, runny or stuffy nose, coughing, wheezing, chest tightness, and exacerbation of asthma leading to shortness of breath. In AERD, such reactions often occur in a significant proportion of cases, with rhinitis reported in 5–10% and bronchial asthma in 10% of affected patients.^[4]^[20]^[1] Dermatological signs present as skin reactions such as hives (urticaria), angioedema (Quincke's edema), flushing, itching, redness, or rashes, which may flare in sensitive individuals. These manifestations affect approximately 20–30% of cases and can appear as chronic if exposure persists.^[1]^[19]^[4] Gastrointestinal effects encompass nausea, vomiting, abdominal pain, diarrhea, bloating, gas, reflux, or chronic intestinal irritation such as colitis. These symptoms occur in 2-7% of reported cases and may contribute to ongoing discomfort with repeated exposure.^[1]^[19]^[4] Other symptoms can include headaches and, in some instances, tinnitus (ringing in the ears), though these are more commonly associated with higher-dose exposures. In children, behavioral changes such as hyperactivity have been anecdotally reported but remain controversial with limited supporting evidence. Fatigue may also occur as a general sign.^[19]^[21]^[22] Symptoms generally onset within minutes to one hour after exposure and can last for hours, resolving upon removal of the trigger, though chronic signs like nasal polyps may persist or recur.^[23]^[1]

Associated Conditions

Salicylate sensitivity is strongly associated with aspirin-exacerbated respiratory disease (AERD), also known as Samter's triad, which comprises asthma, chronic rhinosinusitis with nasal polyps, and hypersensitivity to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs).^[20] AERD affects approximately 7-10% of adult patients with asthma, with higher rates observed in those with severe asthma or nasal polyposis.^[3] In individuals with salicylate sensitivity, exposure can exacerbate respiratory symptoms and contribute to the persistence of nasal polyps, which often prove refractory to standard treatments without dietary salicylate avoidance.^[24] Elevated rates of salicylate sensitivity are also noted in chronic urticaria, where aspirin and NSAIDs can induce or worsen cutaneous symptoms in up to 20% of affected patients.^[25] Gastrointestinal disorders show notable links, including irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), with dietary salicylates implicated in symptom induction in a subset of cases; for instance, sensitivity occurs in up to 7% of patients with ulcerative colitis.^[26] Other comorbidities include atopic dermatitis, where recent meta-analyses indicate salicylate intolerance in up to 53% of individuals, potentially triggering flares.^[17] Migraines are frequently exacerbated by salicylate exposure in sensitive individuals, with dietary triggers like certain fruits and herbs contributing to headache onset.^[27] Salicylate sensitivity also overlaps with mast cell activation syndrome (MCAS), where altered arachidonic acid metabolism leads to leukotriene predominance and heightened mast cell responses upon exposure.^[28] These associations often exhibit bidirectional influences, wherein salicylate sensitivity can intensify underlying conditions—such as worsening nasal polyposis or urticarial flares—while the presence of comorbidities like AERD or MCAS may amplify susceptibility to salicylates.^[29] In rare cases, particularly among children, high-salicylate diets have been linked to behavioral issues resembling ADHD symptoms, including hyperactivity and irritability, though evidence remains limited to observational reports.^[30]

Diagnosis and Assessment

Clinical Evaluation and History

The clinical evaluation of suspected salicylate sensitivity begins with a comprehensive patient history to establish potential links between exposures and symptom onset, as this non-invasive approach is foundational for guiding further assessment.^[1] A detailed dietary history is essential, focusing on consumption of high-salicylate foods such as berries, spices like curry (containing up to 2180 mg/kg), and fruits like oranges (23 mg/kg), alongside medications including aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs).^[1] Clinicians correlate these exposures with reported symptoms, such as respiratory distress or gastrointestinal upset, noting the timing—often immediate or within hours—to differentiate patterns suggestive of intolerance.^[31] Patients are routinely advised to maintain a symptom diary for 2-4 weeks, logging daily intake of potential triggers and any ensuing reactions to identify consistent patterns.^[32] This tool helps quantify exposure-response relationships, such as worsening nasal congestion after spice consumption, and supports the exclusion of unrelated factors by documenting variability in symptom severity.^[1] During physical examination, clinicians look for indicative signs including nasal polyps (present in up to 30% of cases), wheezing indicative of bronchoconstriction, and skin manifestations like rashes or urticaria, which may appear during acute episodes.^[1]^[4] These findings, often confirmed via nasal endoscopy revealing bilateral polyps or auscultation detecting wheezing, provide objective correlates to the history.^[31] Inquiry into family history plays a role in assessing genetic predisposition, with approximately 6% of affected individuals reporting familial aspirin hypersensitivity, suggesting heritable factors in arachidonic acid metabolism.^[33] To exclude confounders like true IgE-mediated allergies, evaluation emphasizes the absence of antigen-antibody responses; salicylate sensitivity manifests as a pseudoallergic reaction driven by eicosanoid imbalances rather than immunoglobulin E involvement.^[1]^[34]

Diagnostic Tests and Challenges

Diagnosing salicylate sensitivity relies primarily on provocative testing methods, as no definitive laboratory biomarkers exist. The gold standard for confirming dietary salicylate intolerance involves an elimination diet trial, typically following the Royal Prince Alfred Hospital (RPAH) protocol, which restricts high-salicylate foods, amines, and additives for 2-6 weeks to achieve symptom stabilization before controlled reintroduction to provoke reactions.^[35]^[36] During reintroduction, incremental challenges with salicylate-containing foods (e.g., starting with low doses like pears or golden delicious apples) are monitored for recurrence of symptoms such as hives, gastrointestinal distress, or respiratory issues, confirming sensitivity if reactions align with prior patterns.^[35] For aspirin-exacerbated respiratory disease (AERD), a subtype of salicylate sensitivity, an oral aspirin challenge serves as a confirmatory test in a supervised clinical setting. This involves incremental dosing starting at 20-40 mg, escalating to 325 mg over 1-2 days while monitoring forced expiratory volume in 1 second (FEV1) for drops exceeding 20%, alongside symptoms like nasal congestion or bronchospasm; nasal or bronchial provocation variants may be used for patients unable to tolerate oral administration.^[37] Challenges require baseline FEV1 ≥70% predicted and are performed under specialist oversight with rescue medications (e.g., albuterol) available.^[37] No reliable biomarkers, such as specific blood tests, exist for salicylate sensitivity, limiting objective diagnosis to clinical provocation. Urinary leukotriene levels may elevate post-challenge in AERD cases but lack diagnostic specificity and are not routinely used.^[38]^[39] Diagnostic challenges include the risk of severe anaphylactoid reactions during challenges, necessitating specialist facilities and contraindications like unstable asthma or pregnancy.^[37] False negatives can occur in mild or intermittent cases due to variable symptom expression, while the absence of biomarkers complicates verification without provocation.^[40] Differential diagnosis requires ruling out overlapping sensitivities, such as to sulfites (common in wines and preservatives, provoking bronchoconstriction at doses as low as 4.6 mg in highly sensitive individuals) or tartrazine (a yellow dye triggering similar reactions at 3.4 mg thresholds), through targeted exclusion or separate challenges.^[41]^[40] These distinctions are critical, as salicylate reactions involve cyclooxygenase inhibition and leukotriene overproduction, unlike the direct pseudoallergic mechanisms of sulfites or tartrazine.^[40]

Management and Treatment

Dietary Interventions

The primary dietary intervention for managing salicylate sensitivity involves adopting a low-salicylate diet, which restricts intake of foods high in naturally occurring salicylates while permitting those with negligible or low levels. This approach is based on quantitative assessments of salicylate content in over 300 food items, revealing high concentrations in certain fruits like oranges (approximately 2.39 mg/100 g), berries such as raspberries (5.14 mg/100 g), and nuts including almonds (3.0 mg/100 g), as well as beverages like tea (4.78 mg/100 mL) and spices such as curry powder (218 mg/100 g).^[42] In contrast, allowable foods include pears (0.27 mg/100 g with skin), white rice (negligible at 0.39 mg/kg), celery, lettuce, and bamboo shoots (all 0 mg/100 g), enabling a balanced intake without complete elimination of plant-based foods.^[42]^[43] The Feingold Diet, introduced in the 1970s, provides a structured protocol originally aimed at reducing hyperactivity but applicable to salicylate sensitivity by eliminating salicylates alongside artificial flavors, colors, and preservatives.^[44] This diet categorizes foods into phases, starting with strict avoidance of high-salicylate items and progressing to reintroduction for tolerance testing. Modified versions, such as the Failsafe Diet developed by the Royal Prince Alfred Hospital, extend this by also limiting amines and flavor enhancers while emphasizing "safe" low-salicylate options like white potatoes and cabbage to support long-term adherence.^[45] Practical implementation requires careful meal planning, such as preparing simple dishes with permitted staples like plain meats, eggs, and low-salicylate grains, while scrutinizing labels for hidden sources including mint flavorings in gums or herbal teas and curry spices in prepared sauces. Supplementation may be necessary to address potential gaps, using low-salicylate forms like ascorbic acid for vitamin C or plain multivitamins without fruit-derived additives. The diet typically begins with a strict elimination phase lasting 4-6 weeks, followed by gradual reintroduction and ongoing monitoring of symptoms through food diaries to identify personal thresholds.^[38]^[6] Clinical studies indicate that adherence to a personalized low-salicylate diet can reduce symptom severity in sensitive individuals, with one trial reporting significant improvements in asthma, rhinosinusitis, and urticaria for 73% of participants after 2-4 weeks. However, challenges include maintaining nutritional balance due to restricted fruits and vegetables, which may lead to deficiencies in vitamins and fiber if not managed with substitutes like cabbage or supplementation, as well as social difficulties from dining out or family meals. Long-term compliance demands professional guidance from dietitians to mitigate these risks and ensure sustainability.^[6]^[46]

Pharmacological and Other Therapies

Leukotriene modifiers, including montelukast and zafirlukast, are commonly prescribed to inhibit the overproduction of leukotrienes, which play a central role in the inflammatory response of salicylate sensitivity, especially in aspirin-exacerbated respiratory disease (AERD). These receptor antagonists reduce nasal congestion, improve asthma control, and attenuate reactions to aspirin exposure by blocking cysteinyl leukotriene pathways.^[47] Clinical studies indicate they are effective in managing symptoms for a substantial portion of AERD patients, with montelukast demonstrating reductions in upper airway symptoms during aspirin challenges.^[48] Zafirlukast similarly contributes to symptom relief, though evidence is more limited compared to montelukast.^[49] For pain management in patients with salicylate sensitivity, alternatives to traditional nonsteroidal anti-inflammatory drugs (NSAIDs) are essential to avoid exacerbations. Selective cyclooxygenase-2 (COX-2) inhibitors like celecoxib are generally safer in AERD, as they exhibit minimal cross-reactivity with aspirin and do not typically provoke respiratory symptoms.^[50] However, caution is advised due to potential variability in individual responses, and celecoxib should be used at the lowest effective dose. Acetaminophen serves as a first-line option for mild to moderate pain, with most AERD patients tolerating doses up to 500 mg without adverse effects.^[4] Aspirin desensitization protocols represent a targeted therapy for AERD-associated salicylate sensitivity, involving supervised gradual escalation of aspirin doses to induce tolerance. Standard protocols administer escalating doses over hours to days, culminating in maintenance therapy of 325–650 mg twice daily, which stabilizes upper and lower respiratory symptoms in the majority of patients.^[51] This approach achieves long-term tolerance in approximately 80% of cases, reducing nasal polyp burden and asthma exacerbations while improving quality of life.^[52] Desensitization is performed in specialized centers with monitoring for reactions, often preceded by leukotriene modifier pretreatment.^[53] Adjunctive therapies address specific manifestations of salicylate sensitivity beyond core inflammation. Antihistamines, such as cetirizine or loratadine, are effective for controlling urticaria and angioedema triggered by salicylates, providing symptomatic relief by blocking histamine-mediated responses.^[25] In refractory AERD with persistent nasal polyps, biologics like dupilumab, an interleukin-4 and interleukin-13 inhibitor, serve as an adjunct to surgery or standard care, significantly reducing polyp size and improving sinus outcomes.^[54] Dupilumab has demonstrated rapid efficacy in AERD cohorts, preventing polyp recurrence post-endoscopic sinus surgery.^[55] Emerging pharmacological options include 5-lipoxygenase inhibitors like zileuton, which directly suppress leukotriene synthesis upstream of receptor antagonists, offering additive benefits in AERD symptom control and potentially reducing the need for sinus surgeries.^[56] Preliminary research explores microbiome modulation as a novel adjunct, investigating how gut or sinonasal microbial alterations might influence inflammatory pathways in salicylate-sensitive conditions, though clinical applications remain investigational.^[57]

Epidemiology

Prevalence and Incidence

Salicylate sensitivity affects an estimated 1-2.5% of the general population worldwide, with prevalence data primarily derived from European studies indicating up to 2.5% in that region.^[21]^[1] This rate is higher in specific at-risk groups, such as those with asthma, where incidence ranges from 2-22%, and in aspirin-exacerbated respiratory disease (AERD), affecting 5-20% of asthmatics depending on diagnostic methods like oral provocation testing.^[58]^[59] Up to 20-40% of patients with chronic urticaria may experience exacerbations from salicylates or related non-steroidal anti-inflammatory drugs.^[25]^[60] Recent analyses highlight elevated rates in other conditions: a 2025 meta-analysis reported a pooled prevalence of 53% for salicylate intolerance among individuals with atopic dermatitis, based on low-certainty evidence from clinical trials.^[17] In irritable bowel syndrome (IBS), prevalence is estimated at 2-7%, while 15-20% of patients with chronic rhinitis or nasal polyps show sensitivity, often linked to pseudo-allergic reactions.^[61]^[26] These figures underscore the condition's association with inflammatory and allergic disorders, though exact incidence varies by diagnostic criteria. Salicylate sensitivity is likely underdiagnosed due to the absence of standardized laboratory tests, relying instead on challenge tests or elimination diets that are not routinely performed.^[38] Incidence appears stable over time, but recognition has increased since the 2010s through expanded research on food chemicals and intolerance mechanisms.^[62] Reports are more frequent in developed countries, potentially attributable to diets rich in processed foods containing added salicylates and greater clinical awareness.^[63]

Demographic and Geographic Patterns

Salicylate sensitivity exhibits distinct patterns across age groups and sexes, with the majority of cases manifesting in adulthood. The condition peaks between 30 and 50 years of age, as evidenced by mean patient ages around 46 years in cohorts with related respiratory symptoms like chronic rhinosinusitis with nasal polyps.^[64] Pediatric cases, though less common, are frequently associated with behavioral symptoms such as hyperactivity, irritability, and inappropriate laughter, often prompting elimination diets for management.^[22] Regarding sex distribution, overall reports indicate a slight male predominance in certain populations, such as in New Zealand, where affected individuals are marginally more likely to be men.^[21] However, in aspirin-exacerbated respiratory disease (AERD), a subset of salicylate sensitivity, females comprise the majority, often comprising 68% or more of diagnosed cases.^[65] Geographic and ethnic variations highlight higher recognition of salicylate sensitivity in Western populations, particularly in Europe and New Zealand, where dietary exposures to salicylate-rich plants are more commonly implicated in symptoms.^[1] In contrast, reports from Asian regions, such as East Asia, appear lower, potentially attributable to dietary differences with reduced intake of high-salicylate herbs and spices or underdiagnosis due to differing clinical focus on other pseudoallergens.^[66] Ethnic patterns are less well-documented, but variations in food production and cultural diets influence exposure levels, with plant-based salicylates more prominent in regions favoring fruits, vegetables, and spices.^[61] Socioeconomic factors contribute to observed disparities, with higher rates in urban settings linked to greater consumption of processed foods that may contain added salicylates or related compounds.^[67] Access to low-salicylate diets is uneven, as maintaining such restrictions can be challenging for lower-income groups due to limited availability of suitable foods and nutritional guidance.^[68] Comorbidity patterns underscore elevated salicylate sensitivity among atopics, where up to 53% of individuals with atopic dermatitis experience flares linked to salicylate intake, often manifesting as food-induced rashes.^[17] In inflammatory bowel disease (IBD) cohorts, overlap occurs in approximately 2-7% of cases, complicating symptom management in those with gastrointestinal hypersensitivity.^[69] Recent data from the 2020s indicate rising awareness, particularly in mast cell activation syndrome (MCAS) patients, where salicylates are increasingly recognized as triggers exacerbating multisystem symptoms.^[27]

Historical Development

Early Discoveries

The use of willow bark, a natural source of salicylates, dates back thousands of years in various ancient cultures for alleviating pain and inflammation. In ancient Egypt, around 1550 BCE, the Ebers Papyrus documented willow leaves as a remedy for treating inflammatory conditions and wounds.^[70] Similarly, Sumerian clay tablets from approximately 4000 years ago referenced willow for pain relief.^[71] In ancient Greece, Hippocrates, often regarded as the father of medicine, prescribed willow bark tea around 400 BCE to ease childbirth pains and reduce fever in women.^[72] Native American tribes also employed willow bark infusions for centuries to treat headaches, fever, and rheumatic pains, recognizing its analgesic properties through traditional herbal practices.^[73] Advances in the 19th century marked the scientific isolation of salicylate compounds from willow bark. In 1828, German pharmacologist Johann Andreas Buchner successfully extracted a bitter, crystalline substance from willow bark, naming it salicin after the Latin term for willow, Salix.^[71] This glucoside was further refined by French pharmacist Henri Leroux in 1829, who isolated it in purer form for potential therapeutic use.^[74] Building on this, Italian chemist Raffaele Piria, working in Paris, hydrolyzed salicin in 1838 to yield salicylic acid, a more potent acidic derivative responsible for the bark's anti-inflammatory effects.^[74] These isolations laid the groundwork for understanding salicylates' pharmacological potential, though early applications were limited by the compounds' irritancy to the stomach. The development of aspirin represented a pivotal refinement in salicylate utilization. In 1897, German chemist Felix Hoffmann at Bayer Laboratories synthesized acetylsalicylic acid by acetylating salicylic acid with acetic anhydride, creating a more stable and tolerable form that reduced gastric side effects.^[75] This compound was patented and marketed by Bayer in 1899 as Aspirin, rapidly gaining popularity as an over-the-counter analgesic and antipyretic.^[75] Early observations of adverse reactions to salicylates emerged shortly after aspirin's introduction. In 1902, German physician Viktor G. S. Hirschberg reported the first documented case of an idiosyncratic hypersensitivity reaction, describing acute urticaria and angioedema occurring within hours of aspirin ingestion in a patient.^[9] Such reports, termed "idiosyncratic" at the time, highlighted rare but severe cutaneous responses, prompting initial medical caution regarding individual variability in salicylate tolerance.^[76]

Modern Recognition and Research

In the early 20th century, respiratory reactions to aspirin were first described. In 1922, French physicians Maurice Widal, P. Abrami, and J. Lermoyez reported cases of severe asthma exacerbations in patients with asthma and nasal polyps following aspirin intake, marking an initial recognition of respiratory hypersensitivity.^[77] However, these observations remained sporadic until the mid-20th century. In the 1960s and 1970s, salicylate sensitivity gained recognition primarily through its association with aspirin intolerance in patients with asthma and nasal polyps. Early clinical observations linked aspirin ingestion to acute respiratory exacerbations in asthmatics, with a 1967 study by Samter and Beers characterizing the condition as a distinct triad involving asthma, nasal polyposis, and hypersensitivity to aspirin, now known as Samter's triad.^[78] Subsequent research in 1975 by Szczeklik et al. demonstrated that aspirin-induced asthma attacks resulted from inhibition of prostaglandin biosynthesis, establishing the reaction as non-allergic in nature and involving altered arachidonic acid metabolism rather than IgE-mediated mechanisms.^[79] This period marked a shift from viewing the sensitivity as idiosyncratic to understanding it as a pseudoallergic response driven by biochemical imbalances. The 1980s brought advancements in quantifying dietary salicylates and exploring their role beyond pharmaceuticals. Anne Swain and colleagues published a seminal 1985 analysis measuring salicylate levels in 333 food items using high-performance liquid chromatography, revealing high concentrations in fruits (e.g., berries and dried fruits), herbs (e.g., curry powder and thyme), and beverages like tea, while cereals, meats, and dairy showed negligible amounts.^[42] This work facilitated the development of low-salicylate diets. Concurrently, the Feingold diet, initially proposed in the 1970s for hyperactivity, gained popularity in the 1980s by eliminating salicylates alongside artificial additives, though subsequent reviews highlighted its controversial efficacy, with limited evidence supporting salicylate elimination as a primary intervention for behavioral disorders.^[44] During the 1990s and 2000s, the condition was more precisely defined, and mechanistic insights deepened. In 1999, Szczeklik's review formalized aspirin-exacerbated respiratory disease (AERD) as the clinical triad of asthma, chronic rhinosinusitis with nasal polyps, and respiratory reactions to COX-1 inhibitors like aspirin.^[77] Building on this, Szczeklik's research in the 2000s elucidated the COX inhibition pathway, showing that aspirin selectively blocks COX-1, reducing protective prostaglandins (e.g., PGE₂) and shunting arachidonic acid toward overproduction of pro-inflammatory cysteinyl leukotrienes via the 5-lipoxygenase pathway, with urinary LTE₄ levels elevated 2- to 10-fold in affected patients.^[77] A 2009 review further outlined the pathophysiology, emphasizing eicosanoid dysregulation and pseudoallergic activation of inflammatory cells without immunological specificity.^[1] From the 2010s to 2025, research expanded into genetics, treatment standardization, and broader intolerances. Genetic studies identified polymorphisms in leukotriene-related genes, such as LTC₄ synthase and CYSLTR2, increasing AERD susceptibility and FEV₁ decline post-aspirin challenge, with a 2016 review highlighting thromboxane A₂ receptor variants as risk factors.^[80] Desensitization protocols were standardized in the 2010s, evolving to efficient one-day regimens (e.g., 90-minute oral escalations starting at 40.5 mg aspirin) that safely induce tolerance in stable AERD patients with FEV₁ ≥70%, reducing polyp burden and steroid use.^[81] A 2025 meta-analysis of four studies (n=188) reported a 53% prevalence of salicylate intolerance in atopic dermatitis flares (95% CI: 44–62%), providing low-certainty evidence of atopic links and calling for refined dietary challenges.^[17] Ongoing microbiome research post-2020 explores gut dysbiosis in food chemical intolerances, including salicylates, with cohort studies linking microbial profiles to symptom persistence, though causal mechanisms remain under investigation.^[82] Increased focus on food intolerances since 2020 has integrated these findings into nutritional concerns, emphasizing non-immune reactions in chronic conditions.^[82]

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Potential genetic biomarkers contributing to the AERD phenotype include HLA-DPB1, LTC4S, ALOX5, CYSLT, PGE2, TBXA2R, TBX21, MS4A2, IL10, ACE, IL13, KIF3A, ...Missing: salicylate | Show results with:salicylate
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Our findings show that the HLA-DPB1 gene polymorphism may be the most susceptible genetic factor for the risk of AERD in Korean asthmatics and confirm the ...
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Aspirin-exacerbated respiratory disease (AERD) refers to aspirin sensitivity, chronic rhinosinusitis (CRS), nasal polyposis, asthma, eosinophil inflammation.6. Therapies · 6.1. Aspirin Desensitization · 6.2. Leukotriene Modifier...
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This sensitivity usually manifests as respiratory reactions that occur upon ingesting or inhaling an NSAID, though the exact cause of the reactions is not known ...Missing: salicylate | Show results with:salicylate<|separator|>
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