1. Understand the Difference between Local and Systemic Reactions Michael S. Blaiss, MD Clinical Professor of Pediatrics and Medicine University of Tennessee Health Science Center Memphis, Tennessee

2. Allergen Immunotherapy Reactions Subcutaneous immunotherapy (SCIT) – Local Large Local Biphasic – Systemic Sublingual Immunotherapy (SLIT) – Local – Systemic

3. Subcutaneous Immunotherapy Adverse Reactions Local SCIT reactions Erythema, pruritus and swelling at the injection site Very common: ranging from 26% to 82% of patients and 0.7% to 16% of injections. 1 92% of A/I adjust for LR in concern for LR/SR or pt will discontinue 2 1.Calabria et al., J Allergy Clin Immunol. 2009;124:739-44 2.Coop et al, Ann Allergy Asthma Immunol. 2008;101(1):96- 100. 3. Tankersley MS. Curr Allergy Asthma Rep. 2011;11(2):115-214. 3

4. Local reactions ‘pearls/myths’ Small or large LR rate defined as ≤ or > palm of hand). 1 – Not related to glycerin content but – Small LR rate higher with increasing allergen content. LLR found not to be predictive of local or systemic reactions with subsequent injections 2-4 Survey of 249 SCIT patients- those who experienced LR 5 – 81.9% deemed LR not to be bothersome. – 96.0% stated they would not stop SCIT because of these LR 1. Calabria et al., J Allergy Clin Immunol. 2008;121:222-6. 2. Calabria et al., J Allergy Clin Immunol. 2009;124:739-44. 3. Tankersley et al, J Allergy Clin Immunol. 2000;106(5):840-3. 4.Kelso Ann Allergy Asthma Immunol. 2004;92(2):225-7. 5. Coop et al, Ann Allergy Asthma Immunol. 2008;101(1):96-100

5. Subcutaneous Immunotherapy Systemic Reactions SCIT SR rate varies greatly depending on several factors: allergen dose, extract type, induction schedule, premeditation, etc. SR rate: review of SCIT studies that reported SR rate: 1 – Per injection frequency was ~0.2% – Per patient rate of 2% in most US studies & 5% (mean) in Europe Signs and symptoms of the SR: One 1 year retrospective survey of 31/773 (4%) subjects had 32 SR in ~28,000 injections (.1%), the symptoms frequency was: 2 – Generalized pruritus ( 34.4%); upper airway pruritus (28.1%); cough( 25.0%); shortness of breath ( 21.9%). 1.Cox L, et al J Allergy Clin Immunol. 2010;125(3):569-74 2.Phillips JF, Lockey RF, et al Systemic reactions to subcutaneous allergen immunotherapy and the response to epinephrine. Allergy Asthma Proc. 2011;32(4):288-94.

6. Cox et al, J Allergy Clin Immunol 2010;125:569-74

7. Worse Case Scenario Subcutaneous Immunotherapy Fatalities 3 surveys of AAAAI members on immunotherapy fatalities spanning time period between 1945-2001

8. Timing of SCIT Systemic Reactions Some studies report up to 50% of SR have be reported to occur beyond the 30 minute wait period recommended by JTFPP & EACCI Most serious SR occur within 30 minutes 1,2 1-year survey of 733 pts on SCIT: 22% of the SR occurred beyond 30 minutes. 3 1.Cox L, et al J Allergy Clin Immunol. 2010;125(3):569-74 2.Tinkleman et al, JAllergy Clin Immunol. 1995;95 3 Phillips JF, Lockey RF, et al. 2011;32(4):288-94.

9. Timing of SCIT Systemic Reactions & Potential Risk Factors 7-years retrospective study to determine whether a pattern of greater skin test reactivity is associated with elevated risk for systemic reaction. Results: 20 patients had 46 SR in 16,375 injections – SR rate was 0.28% per injection visit. – 72% of SR patients had prior SR: 9/15 cases had 2-7 prior SR. – SR risk 6 times higher for patients with > 33% 3 to 4+ SPT (OR = 5.83; 95%CI: 1.23-27.59, P =.026). All severe reactions occurred within 30 minutes. DaVeiga st al,. Systemic reactions associated with subcutaneous allergen immunotherapy: timing and risk assessment. Ann Allergy Asthma Immunol. 2011;106(6):533-7.

10. AAAAI/ACAAI IT Safety Survey July 2010-July 2011 Response rates were down with 518 respondents representing 1,135 prescribers in 2010-11 (630 in previous year) Some important novel findings discovered in Year 3 include: Practices reporting routinely antihistamine premedication were also more likely to have reported injection related SR. Practices never or sometimes reducing allergen doses following LLR were no more likely to experience injection related SR than practices who adjusted doses. Practices who always adjusted allergen doses during peak pollen seasons were significantly less likely to experience moderate or severe SR to allergen injections. Personal communication David Bernstein; publication in preparation

11. Wait Period & Delayed reactions The recommendation that a patient should remain in the physician’s office/medical clinic for 30 minutes after the injection is unchanged from the previous update. It is recommended that at the onset of immunotherapy, patients should be counseled on the possibility of immediate and delayed systemic reactions during risk communication; an action plan for such an event should be discussed. The decision to prescribe epinephrine autoinjectors to patients receiving immunotherapy should be at the physician’s discretion. 11 Cox L, Nelson H, Lockey R, Calabria C, Chacko T, Finegold I, et al. Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol. 2011;127(1 Suppl):S1-55.

12. SCIT Accelerated Schedules Rush Immunotherapy – Rush incremental doses of allergen at intervals varying between 15 and 60 minutes over 1 to 3 days Cluster Immunotherapy – Cluster entails administering several injections at increasing doses (generally 2-3 per visit) sequentially in a single day of treatment on nonconsecutive days

13. Advantages & Disadvantages of Accelerated Immunotherapy Schedules* *Cox L. Advantages & disadvantages of accelerated immunotherapy schedules. J Allergy Clin Immunol 2008; 122:432-4. 2 *

14. Higher Systemic reaction rate with aeroallergen cluster immunotherapy in a clinical practice Risk factors for a systemic reaction included: female sex, asthma, age 21 to 40 years, and inclusion of certain allergens in the immunotherapy vaccine. Conclusions Cluster buildup may lead to a higher rate of systemic reactions. Identifying risk factors for systemic reactions will help improve the safety of cluster immunotherapy. Copenhaver et al. Ann Allergy Asthma Immunol. 2011;107(5):441-7..

15. Subcutaneous Immunotherapy Safety Summary Incidence of SRs dependent on multiple factors at a rate ~0.2% of injections and 2-5% of patients Delayed & biphasic do occur not infrequently Fatalities rare in previous surveys but none in ~24 million injection visits from June 2008-July 2011 WAO Grading System for classifying systemic reactions: Aeroallergen RIT higher rate of SR even with premedication Cluster SR rater appears similar to conventional but more studies needed with multiallergen SCIT. Premedication – Reduces LR and SR with conventional & accelerated IT schedules – Recommended for aeroallergen RIT – Does not appear to be needed for VIT Caution with ACE- inhibitor & beta-blockers including β 1 -selective

16. Sublingual Immunotherapy Safety Some difficulty in evaluating SLIT safety because: – Treatment administered at home – Thus adverse reactions primarily occur at home, i.e., unwitnessed and/or not evaluated by a someone with medical training – May be significant variability in accuracy and interpretation of patient’s reported AEs

17. AAAAI/ACAAI JTF Summary of SLIT Adverse Events In 66 SLIT studies AE there were no fatalities or anaphylactic reactions accompanied by hypotension – 1,181,000 doses of unmodified allergen to 4765 patients No reports of SLIT-related fatalities Oral-mucosal symptoms: affecting up to 75% of patients Systemic Rx: 0.56 SR per 1000 SLIT doses – No clear predictors for SLIT adverse reactions (e.g., dose, induction schedule, asthma etc.) ‘ 14 probable SLIT SAE: 7 asthma-1 hospitalized Post JTF report:4 cases of anaphylaxis in the published literature: 2 hospitalized and 1 with LOC (B/P 70/40)

18. Treatment-Related Adverse Events in ≥5% of Subjects Adult StudiesPediatric Studies Treatment-Related Adverse Event, n (%) Grass AIT (n=1060) Placebo (n=1036) Grass AIT (n=302) Placebo (n=296) Oral pruritus409 (39%)47 (5%)107 (35%)9 (3%) Throat irritation227 (21%)26 (3%)75 (25%)7 (2%) Ear pruritus145 (14%)10 (1%)25 (8%)1 (<1%) Mouth edema121 (11%)6 (<1%)23 (8%)1 (<1%) Oral paresthesia86 (8%)13 (1%)N/A Stomatitis * N/A 26 (9%)2 (1%) Lip swelling N/A 21 (7%)0 N/A=not applicable; AE was experienced by <5% of subjects. *Indicates mild erythema, not lesions or infection. 18 Most treatment-related adverse events were transient oropharyngeal reactions Local oropharyngeal reactions rarely (<4%) led to discontinuation

19. Most Local Adverse Events Occur During the First Month of Treatment Median onset for local AEs with grass AIT ranged from 1–5 days for adults and 1–8 days for children Median number of days that local AEs were reported with grass AIT ranged from 4–30 days for adults and 2–17 days for children Adult StudiesPediatric Studies Median Day of Onset Median Number of DaysMedian Day of Onset Median Number of Days Adverse Event Grass AIT (n=1060) Placebo (n=1036) Grass AIT (n=1060) Placebo (n=1036) Grass AIT (n=302) Placebo (n=296) Grass AIT (n=302) Placebo (n=296) Oral pruritus11821151 Throat irritation11631141 Ear pruritus123421161 Mouth edema5130182171 Oral paresthesia11102N/A Stomatitis * N/A 15321 Lip swellingN/A 3—2— N/A=not applicable; incidence was <5%. * Indicates mild erythema, not lesions or infection. 19

20. Two Cases SLIT Anaphylaxis with First Grass Table Dose 17 yo male d/c grass SCIT due to SR-developed urticaria, facial and tongue angioedema within15 minutes 1 st grass tablet 24 yo female with AR & asthma also d/c grass SCIT due SRs – After 1st grass tablet taken at home, she immediately experienced asthma sx, generalized itching, faintness and abdominal cramps; she recognized this from the SCIT side effect, but felt much worse ! – She took a lot of antihistamines, ICS & sympaticomimetica, and rushed to the GP office; – In distress on arrival: wheezing, pale, nearly fainting, BP 90/50 mmHg. Given adrenaline. – She recovered in the next few hours. 20 de Groot H, Bijl A. Anaphylactic reaction after the first dose of sublingual immunotherapy with grass pollen tablet. Allergy 2009; 64:963-4.

21. WAO Grading System for SLIT Local Reactions Passalacqua et al, Grading side effects of sublingual immunotherapy speaking the same language. 2011 in preparation

22. Sublingual Immunotherapy Safety Summary SLIT appears to be better tolerated than SCIT Majority of SLIT AE’s are oromucosal & occur during the beginning of treatment A few cases of SLIT-related anaphylaxis have been reported but no fatalities Risk factors for the occurrence of SLIT SAE have not yet been established Proposed WAO system of for reporting SLIT adverse local reactions WAO grading system for SCIT systemic reactions to be used for SLIT SR with exception of GI and some upper respiratory symptoms WAO SLIT Position Paper Paris 2009

23. Sublingual Immunotherapy Safety: Unmet Needs Answered/Partially Answered The safety of SLIT in patients who have had SR with SCIT The safety of SLIT with multiple allergens Interruptions in treatment: how long between doses is it safe to administer usual dose? Is it safe to administer SLIT with no induction with all formulations? Canonica GW, Bousquet J, Casale T, Lockey RF, Baena-Cagnani CE, Pawankar R, et al. Sub-lingual immunotherapy: World Allergy Organization Position Paper 2009. Allergy. 2009;64 Suppl 91:1-59.

24. Sublingual Immunotherapy Safety: Still Unmet Needs The safety of SLIT in moderate to severe asthmatics.? Are oropharyngeal infections or lesions risk factors for SLIT SRs? Under which clinical situations should an SLIT dose be withheld? The safety of SLIT in pregnant or breast or feeding women. The safety of SLIT in patients on beta-blockers. Are there any risk factors that identify which patients may experience a SR with SLIT? Canonica GW, Bousquet J, Casale T, Lockey RF, Baena-Cagnani CE, Pawankar R, et al. Sub-lingual immunotherapy: World Allergy Organization Position Paper 2009. Allergy. 2009;64 Suppl 91:1-59.

25. In conclusion Physicians administering immunotherapy need to be aware of the possibility of local and systemic reactions In general, systemic reactions are higher in SCIT but local reactions are very common in SLIT Patients must be knowledgeable on local and systemic reactions to improve adherence to immunotherapy