Overview of ASA/NSAID Hypersensitivity


COX-1 Inhibitors

Strong inhibitors of COX-1
  • Universal cross-reactions between these NSAIDs occur
  • At high concentration, inhibit COX-2
Poor inhibitors of COX-1
  • At high concentrations minimal inhibition of COX-1, without inhibition of COX-2
Preferentially inhibit COX-2 at lower doses but partially inhibit COX-1 at higher doses
Selective COX-2 inhibitors
  • Preferentially inhibit COX-2 at prescribed doses, no inhibition of COX-1 occur
  • Acetylsalicylic acid (Aspirin)
  • Ibuprofen
  • Naproxen
  • Ketorolac
  • Indomethacin
  • Etodolac
  • Diclofenac
  • Piroxicam
  • Sulindac
  • Tolmetin
  • Fenoprofen
  • Oxaprozin
  • Mefanamic acid
  • Flurbiprofen
  • Difluinisal
  • Ketoprofen
  • Nabumetone
  • Acetaminophen (paracetamol)
    • Relatively safe alternative for almost all patients with AERD
    • High doses (≥1000 mg) have been reported to provoke
      easily reversed bronchospasm in some with AERD
  • Salsalate
  • Nimesulide
  • Meloxicam (≥15 mg)
  • Available in US
    • Celecoxib
  • Not available in US
    • Etoricoxib
    • Parecoxib
    • Lumiracoxib
  • Pulled from US market
    • Rofecoxib
    • Valdecoxib

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Aspirin-Exacerbated Respiratory Disease (AERD)


  • Affects up to 0.9% of general population, up to 20% of asthmatics, and up to 40% of asthmatics with nasal polyps
  • Onset: teenage years - middle adulthood
AERD Triad
Chronic sinusitis with nasal polyps
  • Nasal congestion with anosmia that progresses to chronic hypertrophic eosinophilic pansinusitis with polyps
  • Polyps regrow rapidly after surgery
  • May precede the sinus disease or occur later
Sensitivity to any medication that inhibits COX-1
  • See COX-1 inhibitors table below
  • Acute ingestion of ASA and most NSAIDs results in upper and/or lower respiratory reactions including rhinitis, conjunctivitis, laryngospasm and bronchospasm

Diagnosis of AERD

  • History of respiratory symptom exacerbation following ASA or NSAID dose is suggestive
    • Borish: diagnosis is AERD clinical features.pngbest supported by a compelling history of upper and/or lower respiratory compromise in response to ASA/NSAIDs occurring on 2 separate occasion
      • ASA/NSAID-induced exacerbations of GERD may trigger upper and lower airways symptoms in the absence of AERD
      • ASA/NSAID-induced urticaria/angioedema is emphatically not associated with AERD
    • Alcohol ingestion causes respiratory reactions in the majority of patients with AERD (typically within 3 glasses and/or 1 hour)
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  • Aspirin challenge is the gold standard for diagnosing AERD
    • Challenge may be performed via oral route (common in US), bronchial inhalation, nasal inhalation (Europe) and IV
    • Diagnosis of aspirin-exacerbated cutaneous disease is based on history; these patients should not undergo challenges with the suspected drugs and should be considered cross-reactors (or multiple reactors), even if they have histories of urticaria induced by a single NSAID
  • CT or plain radiographs of the sinuses reveal complete opacification in nearly all AERD patients; normal imaging of the sinuses essentially rules out AERD
  • Peripheral eosinophilia (when off systemic steroids) is a cardinal feature of AERD, and a patient without this lab finding does not have AERD
  • Urinary leukotriene E4 (LTE4) - more likely to be elevated in AERD, and higher baseline LTE4 values increase risk of reaction during oral ASA challenges. However, urine LTE4 is not diagnostic as many AERD patients have low values.

Treatment of AERD

  • Overall approach (Borish): medical polypectomy (steroid taper x 21 days), followed by maintenance with budesonide/saline sinus rinses, followed by surgical polypectomy if this not effective
  • Anti-leukotriene medications: montelukast may be helpful but zileuton may be especially effective (shown to shrink polyps, improve sinus/asthma symptoms, restore sense of smell in 50%)
  • Aspirin desensitization and daily treatment with aspirin - significantly improves overall symptoms and quality of life, decreases formation of nasal polyps and sinus infections, reduces the need for oral steroids and sinus surgery, and improves nasal and asthma scores in patients with AERD
    • Surgical polypectomy 2-4 weeks before desensitization is ideal because desensitization is most effective in preventing new polyp formation, and procedure may be safer because there is less polyp tissue to produce inflammatory mediators
    • If desensitization not performed, patients must completely avoid COX-1 inhibitors. Even with strict avoidance, most AERD patients develop progressively worsening airway disease
    • Aggressive medical management must be continued after surgery and aspirin desensitization (e.g. zileuton and budesonide nasal saline rinses) to retard polyp regrowth

ASA Challenge and Desensitization Protocol (Scripps Clinic)

  • Typical indications
    • Intractable symptoms despite medical treatment
    • Recurrent nasal polyps requiring multiple surgeries
    • Frequent or daily systemic corticosteroids are required to control nasal symptoms and/or asthma
    • Additional medical indication for aspirin (e.g. antiplatelet therapy for cardiovascular diseases, arthritis)
  • Obtain signed informed consents prior to challenge and desensitization
  • Unstable asthma
    • Patient should have FEV11.5L, >60% predicted, and within 10% of best prior value
  • Pregnancy
  • Gastric ulcers
  • Bleeding disorders
  • Start montelukast 10 mg PO QD 2-4 weeks prior to challenge (if not already taking it)
  • Stabilize asthma and treat all other concomitant conditions that may affect safety, tolerability, and efficacy of desensitization
    • Asthma, AR - oral steroids if necessary, continue all of patient's current medications for upper and lower airways, including inhaled/intranasal steroids
    • Polyps - debulking nasal polyposis 2-4 weeks before desensitization is ideal because desensitization most effective in preventing new polyp formation, and procedure may be safer because there is less polyp tissue to produce inflammatory mediators
    • GERD - consider PPI, H2 blocker, fundoplication if severe
    • Infections (sinus, pulmonary)
  • Stop antihistamines and decongestants 48 hours prior
  • Stop SABA on day of challenge

Oral aspirin challenge
  • Standard method in US
Intranasal ketorolac and modified oral aspirin challenge
  • Preferred method at Scripps Clinic
    • Faster with decreased risk of laryngospasm and GI adverse effects
    • Contraindicated if nasal obstruction due to polyps (but best candidates for ASA desensitization have recent surgical polypectomy)
Prepare challenge materials
  • ASA 81 mg tablets cut with a pill cutter into fourths, halfs, etc
  • ASA 81 mg tablets cut with a pill cutter into fourths, halves, etc
  • Prepare intranasal ketorolac
    • Mix 2 mL of ketorolac tromethamine IV solution (60 mg/2 mL) and 2.75 mL preservative free normal saline in an empty nasal spray bottle that delivers 100 microliters/actuation (e.g. Nasocort AQ bottle)
    • Prime with 5 sprays before use; each 0.1 mL spray = 1.26 mg of ketorolac
    • Tilt head down while spraying and sniff gently to avoid swallowing
    • Sprix (ketorolac nasal spray) approved by FDA and may be useful
Choose challenge setting
  • Safe to perform in outpatient setting
  • Inpatient desensitization should be strongly considered in patients receiving beta-blockers, recent myocardial infarction, and/or with severe/uncontrolled asthma
Placebo challenge day
  • A placebo challenge can be conducted the week before
  • Alternatively, if the patient’s baseline FEV1 is the same as their prior best value and they have not used their albuterol rescue inhaler in the past week, you can skip the placebo challenge
Day 1
  • FEV1 every hour, wait 3 hours between doses
  • Challenge dosing Q3 hours:
    • 8 AM: 20-40 mg PO
    • 11 AM: 40-60 mg PO
    • 2 PM: 60-100 mg PO
    • 5 PM: discharge

  • Most reactions occur at 45-100 mg
  • Choose lower dose if the patient is not using a leukotriene-modifying drug, has a low baseline FEV1, and/or has had a recent hospitalization or ED visit for asthma
  • Clinical and objective evaluation with spirometry performed before each dose and PRN
  • Challenge dosing:
    • 8 AM: 1 spray (in one nostril)
    • 8:30 AM: 2 sprays (1 in each nostril)
    • 9 AM: 4 sprays (2 in each nostril)
    • 9:30 AM: 6 sprays (3 in each nostril)
    • 10:30 AM: 60 mg PO
    • 12 PM: 60 mg PO
    • 3 PM: discharge
Day 2
  • Measure FEV1 every hour and wait 3 hours between doses
  • Challenge dosing Q3 hours:
    • 8 AM: 100-160 mg PO
    • 11 AM: 160-325 mg PO
    • 2 PM: 325 mg PO
    • 5 PM: discharge
  • Challenge dosing:
    • 8 AM: 150 mg PO
    • 11 AM: 325 mg PO
    • 2 PM: discharge
Criteria for positive challenge
  • Positive challenge if any of the following occur:
    • Naso-ocular symptoms
    • Classic reaction - Naso-ocular symptoms and a 15% decline in FEV1
    • Lower respiratory reaction only - FEV1 declines by >20%
    • Laryngospasm (flat or notched inspiratory curve) with or without other symptoms
    • Systemic reaction: hives, flush, gastric pain, hypotension
  • Manage reactions
    • If reaction occurs in larynx or bronchi, treat, wait for resolution, repeat provoking dose, and continue dose escalation Q3 hours
      • Bronchospam - SABA
      • Laryngeal reaction - racemic epinephrine, IM epinephrine
    • If reaction isolated to eyes/nose, may treat, and continue to next scheduled dose
      • Naso-ocular - oxymetazoline nasal spray (e.g. Afrin), PO/topical antihistamines
    • Cutaneous reactions (flushing, urticaria, angioedema) - antihistamines PO/IV
    • Gastric symptoms (nausea, vomiting and abdominal cramping pain) - PO/IV H2-antihistamines
    • Systemic reactions - IVF and IM epinephrine available but rarely needed (0.002%)
  • If positive challenge occur may proceed to desensitization
Criteria for negative challenge
  • Negative challenge if no reaction occurs 3 hours after ASA 325 mg given
  • If patient has not reacted to 325 mg of ASA, they will not react to 650 mg
  • Some consider proceeding with ASA desensitization therapy for a 1 month trial even if there is a negative challenge due to the possibility that a positive challenge was masked by montelukast
  • After positive challenge symptoms are treated/resolved, repeat provoking dose (same dose that caused positive challenge)
  • If no reaction seen with repeat dose, continue to escalate until dose of 325 mg PO reached
  • Once 325 mg PO is tolerated, desensitization is complete: give ASA 650 mg PO as first dose and continue at 650 mg PO BID for at least 1 month
  • Titrate aspirin dose
    • If there is significant improvement after 650 mg PO BID x 1 month, decrease by one tablet (325 mg) each month to 650 mg PO QAM and 325 mg PO QHS, and then ideally decrease again to 325 mg PO BID
    • Titrate dose of ASA down to lowest effective dose (usually 325 mg PO BID)
      • A dose as low as 81 mg PO QD can maintain the desensitized state, which may be sufficient for patients who need only cardiovascular prophylaxis, but is usually suboptimal for treating AERD which requires at least 325 mg PO QD
  • Manage common side effects
    • GERD/ulcer prophylaxis
    • Treat aspirin-induced urticaria with antihistamines
    • A case series suggests that dose-dependent pancreatitis (easily misdiagnosed as gastritis) may occur
  • Interruption of therapy
    • If there are brief interruptions (<48 hours) due to surgery or illness, aspirin may be restarted at previous dose due to a desensitized refractory period (24-72 hours)
    • If >48 hour interruption, recommend repeat desensitization
  • Pregnancy - due to risk of adverse effects on fetus with NSAID use during pregnancy, it may be prudent to discontinue NSAID use then desensitize again after pregnancy

Practice Parameter (2010)

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Approach to Patients with Cardiovascular Disease and ASA Hypersensitivity


  • True IgE-mediated reactions to ASA seem to be non-existent or very rare
  • The goal of the allergist is to safely deliver at least ASA 81 mg (low dose) to the patient requiring this drug for its antiplatelet effect
    • In the CURRENT-OASIS 7 trial, there was no significant difference between ASA 75–100 mg and 300-325 mg on cardiovascular death, MI, and stroke at 30 days
    • In combination with other potent platelet inhibitors (prasugrel and clopidogrel) there are no data to suggest that ASA 325 mg is more efficacious than 81 mg at preventing restenosis in the first 24–48 hours


Scripps Clinic

  • Contraindicated in patients with an unstable arterial lesion (evolving MI, TIA, or CVA, etc.), the intravascular intervention should occur first and considerations for challenge/desensitization should be secondary; this is due to the real possibility of causing asthma (AERD) or histamine-mediated coronary vasospasm
  • Patients with a history of ASA/NSAID induced SJS, TEN, DRESS, allergic interstitial nephritis, serum sickness
  • Relative contraindication for chronic urticaria/angioedema, because this condition may make long term use of ASA/NSAIDs impossible to manage
  • A one-to-one, constant nursing attendance is required, with the supervising physician immediately available
  • At Scripps Clinic, virtually all ASA procedures occur in the outpatient clinic, but it is "recognized that in other clinics/practices this same approach to aspirin challenge/desensitization will be undertaken in a monitored hospital bed"
  • Patients without AERD
    • If the patient is unstable enough that continued hospitalization is required for management of the underlying condition, then premedication with steroids, antihistamines, and montelukast is acceptable even if it prevents diagnosis of hypersensitivity by masking the reaction
    • If the patient is seen as an outpatient, then avoidance of pretreatment is strongly recommended on order to obtain an accurate diagnosis
  • Patients with AERD
    • Montelukast 10 mg, ICS/LABA, systemic corticosteroids ("usually IV"), and antihistamines
    • Obtain baseline spirometry
  • If convincing history of a particularly severe reaction, start with ASA 20.25 mg (1/4 81 mg baby ASA tablet cut with a pill cutter), wait 90 min, repeat 20.25 mg, wait 90 min, then give 40.5 mg, then wait 90 min
  • For other patients, start with ASA 40.5 mg, wait 90 min, then repeat 40.5 mg, then wait 90 min
    • AERD patients most likely will react after the second 40.5 mg dose
  • Discharge patient, who may begin ASA 81 mg PO QD treatment the next day
  • If higher doses are desired by the referring cardiologist, patient may return the next day for additional updosing (start with ASA 121.5 mg, wait 90 min, 202.5 mg, wait 90 min, 325 mg, wait 3 hours)

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  • Choose appropriate protocol according to reaction history
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