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Aspirin-exacerbated respiratory disease for the practicing allergist

Aspirin-exacerbated respiratory disease for the practicing allergist. Kathleen M. Buchheit, MD Assistant Director, AERD Center Allergy & Immunology Brigham and Women’s Hospital September 13, 2019. Conflict of Interest Disclosure.

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Aspirin-exacerbated respiratory disease for the practicing allergist

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  1. Aspirin-exacerbated respiratory disease for the practicing allergist Kathleen M. Buchheit, MD Assistant Director, AERD Center Allergy & Immunology Brigham and Women’s Hospital September 13, 2019

  2. Conflict of Interest Disclosure Relevant financial relationships with commercial interests in the preceding 12 months: Regeneron, Genentech

  3. Learning objectives Review clinical presentation of AERD Discuss mechanisms and pathophysiology Provide updates in diagnosis and management Introduce areas of ongoing study in AERD

  4. Classic AERD = 35 year-old “Danielle” • Childhood  healthy, no asthma or allergies • 23yo  “really bad cold” and persistent nasal congestion • 24yo  asthma, continued congestion, lost sense of smell and taste • 25yo  saw ENT surgeon, was “full of polyps”, had 1st polyp surgery (great improvement!), but polyps returned in 6 months • 25yo Cold-flu tablet – 2 h later sneezed, chest tightness, wheezing •  3 mo later ibuprofen – to ER for albuterol and IV steroids •  6 months later took naproxen – same reaction • Polyp surgeries: 25yo, 27yo, (no surgery while had 2 kids), 33yo, 35yo • Now  Inhaled steroids, montelukast, steroid sprays, loratadine, albuterol 3-4 days/wk, no sense of smell, antibiotics and oral corticosteroids for sinusitis 2-3 times a year, polyps are back

  5. AERD presents with a stereotyped pattern and common phenotype • Not IgE-mediated allergy to aspirin1 • Not Mendelian inheritance2 • Not due to (known) environmental trigger3 • How common is it? • 7% of adults with asthma • 14% of adults with severe asthma • 25% of adults with asthma+polyps • ~ 1.5 million patients in U.S.5

  6. Findings from our cohort of patients at the BWH AERD Center Largely adult-onset disease… Blood eosinophilia is common 42% >500 68% 21-50yo …but there are exceptions. Tuttle KL, et al. JACI-IP 2016

  7. Surgical histories from cohort of patients at the BWH AERD Center Typical appearance of polyps on rhinoscopy, and can be very large Selig, YK. Nasal polyps on rhinoscopy. 2015 Bhattacharyya, N. Nasal polyps excised. 2016 • History of polyp surgery: • 60% have had >2 surgeries • 10% have had >5 surgeries • Rate of polyp regrowth post-op: • 50% report regrowth <6 months • Only 15% report no regrowth >2 years

  8. AERD: Reactions to NSAIDs Classic reaction: • Bronchoconstriction = wheezing, cough, fall in FEV1 • Nasal/ocular symptoms = sneezing, congestion, headache/facial pressure, rhinorrhea, eye tearing, eye redness/swelling Less common: • Rash, urticaria, angioedema • Abdominal pain, nausea, vomiting1 • Average time to reaction is ~60 minutes after aspirin exposure and doses of ≤ 162 mg of aspirin elicited reaction in >95% of patients with AERD.2 *3 – 6% of patients react to ≤ 650 mg acetaminophen3 *34% of patients react to > 1000 mg acetaminophen4

  9. Reactions to NSAIDS involve more extra-pulmonary symptoms than previously thought • Any COX-1 inhibitor can cause reaction: • aspirin, ibuprofen, naproxen, ketorolac are most common in U.S.

  10. Tolerance of COX-2 inhibitors AERD Black Box Warning: “Celecoxib is contraindicated in patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs.” Nine Publications from 6 groups have proven safety of COX-2 inhibitors in AERD. 1 case report of etoricoxib-induced respiratory reaction in AERD.

  11. Tricks to make AERD diagnosis What if you feel like it could be AERD, but patient says “no” to the “Do you have any problems when you take aspirin, ibuprofen, or naproxen?” question: • Patient has not taken aspirin/NSAIDs in a long time • Patient is on 81mg aspirin daily (already desensitized) • Patient is on montelukast or zileuton • Patient is so ridiculously stuffed up with polyps at baseline that they couldn’t even tell if got worse.

  12. Clinical clue: Respiratory reactions to alcohol De Schryver E. Clin&ExperAll 2016 Cardet JC. JACI In Pract. 2014

  13. AERD: Pathophysiology • Dysregulated cysteinyl leukotrienes (CysLT) • Excessive basal CysLT generation • Increase CysLT generation upon COX-1 inhibition • Airway hyperresponsiveness to CysLTs • Baseline levels correlate with severity of aspirin-induced asthma attack • CysLT production may be driven in part by platelet-adherent leukocytes • Mast cell activation • PGD2, histamine, tryptase, leukotrienes • At baseline • During aspirin reaction • Inhibitors of mast cell activation modify reactions to aspirin • Driven in-part by innate type 2 cytokines

  14. COX pathway vs 5-LO pathway Leukotriene pathway COX pathway COX1 / COX2 PGD2 TXA2 PGE2 4 PGE2 receptors (EP1-4) 4 PGE2 receptors (EP1-4)  PGE2  EP2 receptor  PGD2  LTE4  LTC4S  CysLT1R

  15. Effector cells in AERD

  16. Summary: Clinical/mechanistic points • Triad: ask all adult asthmatic patients about nasal polyps, sense of smell, and COX-1 inhibitor tolerance • Can miss diagnosis in patients LTRA or zileuton • Respiratory reactions with all COX-1 inhibitors, some patients also sensitive to acetaminophen, but selective COX-2 inhibitors are tolerated • Disease of dysregulated leukotrienes and mast cell activation  Activation of effector cells including Th2 cells, ILC2s, eosinophils, basophils, and neutrophils/platelets Next: diagnosis and management updates

  17. Aspirin/NSAID challenge is the GOLD STANDARDfor diagnosis of AERD! • Who needs a challenge? • Protocol: • Start at 40.5 mg aspirin • Double dose every 90 – 180 minutes • PFTs prior to every dose and if reaction • Stop at 325 mg aspirin1 • Timing of challenge is important  less sensitive post-operatively2,3

  18. Aspirin reactions are less severe/can be missed following endoscopic sinus surgery1,2

  19. Eicosanoids decrease - at baseline and during aspirin challenge - before and after endoscopic sinus surgery

  20. Tolerance of daily aspirin 81 mg does not preclude (and may delay) AERD diagnosis

  21. Updates in management of AERD • Aspirin desensitization • Leukotriene modification • Biologic therapy • Omalizumab • Anti-IL-5/IL-5Rα • Dupilumab • Dietary intervention

  22. Aspirin desensitization followed by daily, high-dose oral aspirin treatment • 6 mo of ASA = 67% pts improved, 1 yr of ASA = 87% pts improved Stevenson, et al. JACI 1996 • 100% of 7 AERD pts on very low dose aspirin had polyp recurrence within 1 year, 0% of pts on high-dose aspirin had polyp recurrence Rozsasi, et al. Allergy 2008 • 20 AERD patients (8 placebo, 12 on 624mg aspirin QD) – within 6 mo, patients on aspirin had  SNOT-20 & ACQ scores,  PNIF, and 5/8 had return of sense of smell. Nizankowska-Mogilnicka, JACI 2014 • 91% who had been on high-dose aspirin found it “effective” • (but <50% had ever undergone aspirin desensitization) Ta and White, JACI IP, 2015 (190 patients) When to desensitize? Preferably after surgery. What daily aspirin dose to use?650mg vs 1300mg Lee, JACI 2007

  23. Aspirin desensitization and high-dose oral aspirin (to treat) - PROTOCOL Daily aspirin to maintain desensitization –  benefits occur only if aspirin is taken regularly  Challenge 40.5mg 81mg 162.5mg 325mg Provocation of symptoms 325mg 162.5mg 81mg 325mg

  24. Urinary LTE4 (log) Leukotrienes are dysregulated in AERD AERD Aspirin-tolerant asthma High leukotrienes at baseline Even higher after aspirin What medications can we use to decrease the production or effects of leukotrienes? Mastalerz and Szczeklik, Thorax 2008

  25. Use of leukotriene-modifying medications in AERD • Zileuton (5-LO inhibitor) and montelukast(cysLT1 receptor antagonist) improve AERD symptoms at baseline • Zileuton: ↑ FEV1, improves smell, ↓ SABA use • Dahlen B, Szczeklik A et al. AJRCCM 1998 • Montelukast: ↑ FEV1, improves nasal symptoms scores • Dahlen S, et al. AJRCCM 2002 • Micheletto C. Allergy 2004 • For aspirin desensitization: • Montelukast: Blunts fall in FEV1 = Safer desensitization • Zileuton: Can increase provocative dose or block reactions completely • Useful for gastrointestinal reactions during desensitization • 28% found zileuton “extremely effective” • (only 24% had ever been on zileuton) • 15% found montelukast “extremely effective” • (almost 90% had been on one of these) Ta and White, JACI IP, 2015 (190 patients)

  26. Zileuton is more effective in patients with AERD than in aspirin-tolerant asthma “Efficacy of Zileuton in Patients with Asthma and History of Aspirin Sensitivity: A Retrospective Analysis of Data from Two Phase 3 Studies” % Change in lung function (FEV1) from baseline on Day 85 35% 30% 25% 20% 15% 10% 5% 0 -5% AERD patients AAAAI 2017 Poster L30

  27. Omalizumab decreases urinary LTE4/PGD2 and blunts aspirin-induced reactions in AERD Hayashi H, et al. J Allergy Clin Immunol 2016;137:1685.

  28. Mepolizumab reduces polyp size, sinonasal symptoms and need for surgery Percentage needing surgery Rhinorrhea Mucous SNOT-22 p = 0.005 In AERD: * * * Adjusted mean rhinorrheaVAS scores (cm) * * * * * Percentage of patientsin need of surgery * Adjusted mean mucousin throat VAS scores (cm) * * * * * * 0.5 * * * * * * * * * * * * * SNOT-22 Score 0.0 -0.5 1 1 1 1 Study week Study week Study week TPS Congestion Smell -1.0 * * -1.5 * * * * * * * * * Adjusted mean nasalblockageVAS scores (cm) LS mean change frombaseline in total endoscopic nasal polyp score Adjusted mean loss of smellVAS scores (cm) * * * * * -2.0 * * * * -2.5 Study week Study week Study week 1 1 Placebo Mepolizumab Treatment (95% CI) Bachert C, et al. J Allergy ClinImmunol. 2017;140:1024-31. Double blind placebo controlled, 105 nasal polyp patients total. IV Qmonth for 6 months. *P ≤ 0.05, **P≤0.01, ***P≤0.001

  29. ACQ-5 FEV1 (L) **Dupilumab improves upper and lower airway symptoms in AERD** SNOT-22 Smell/taste Nasal polyp score

  30. Low omega-6 fatty acid diet can decrease leukotrienes and improve symptoms in AERD Good: Wild-caught cold-water fish (salmon, herring, tuna) Fat-free dairy, egg white Leafy green vegetables Most vegetables and fruits Many beans, some grains Bad: Vegetable oils (corn, soybean, safflower) Margarine Meats if animals ate corn/soy Eggs/dairy if animals ate corn/soy Treatment diet decreased LTE4 in the urine Schneider TR, Laidlaw TM. J Allergy Clin Immunol In Pract. 2018

  31. Ongoing clinical studies: AERD • Mechanism of aspirin desensitization in AERD (BWH) • Ifetroban (thromboxane receptor antagonist) • Patients with symptomatic AERD (multi center) • Effect of aspirin challenge (BWH) • Fevipiprant (CRTH2 antagonists) • Dupilumab phase III, mepolizumab phase III, omalizumab phase III • AERD Registry and Biobank (non-BWH patients eligible to participate in Registry)

  32. Summary: AERD diagnosis and treatment • Aspirin challenge is the gold standard for diagnosis in AERD • Stop baby aspirin, montelukast, and antihistamines prior to challenge • Aspirin desensitization followed by high-dose aspirin therapy improves upper and lower airway symptoms • Can safely be carried out using one day protocol • Zileuton and montelukast improve symptoms and lung function • Omalizumab, anti-IL-5/IL-5Rα, and dupilumab • No randomized, placebo-controlled trials in an AERD population

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