1. Specific Allergen Immunotherapy Safety World Allergy Organization 2011 Congress Cancun, Mexico
Linda Cox, MD, FAAAAI, FACAAI
Associate Clinical Professor of Medicine Nova Southeastern University
Ft. Lauderdale, Florida

2. Allergen Immunotherapy Safety
Subcutaneous immunotherapy
Sublingual Immunotherapy
Adverse reactions: types and incidence per published studies ,post marketing surveillance & surveys
Lessons learned from the literature: risk factors
WAO Grading system for SCIT/SLIT systemic reactions and SLIT local reactions
Other forms of immunotherapy
Oral immunotherapy (foods)
Adjuvants/peptides
Epicutaneous/intralympahatic

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 discontinue2 3
1.Calabria et al., J Allergy Clin Immunol. 2009;124: Coop et al, Ann Allergy Asthma Immunol. 2008;101(1): Tankersley MS. Curr Allergy Asthma Rep. 2011;11(2):

4. Subcutaneous Immunotherapy Adverse Reactions
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 LR5
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: Calabria et al., J Allergy Clin Immunol. 2009;124: Tankersley et al, J Allergy Clin Immunol. 2000;106(5): Kelso Ann Allergy Asthma Immunol. 2004;92(2): Coop et al, Ann Allergy Asthma Immunol. 2008;101(1):96-100

5. Individuals with a greater frequency of LLR may be a greater risk for SR
Methods: Retrospective review of a database: comparing LLR rate in pts who had SRs with pts who did not have SRs
LLR= redness & swelling ≥25 mm
Results: 258 pts had 283 SRs in 108,621 injections
LLR rate 4 times higher in pts with SRs than pts with no SRs
SR group: LLR rate: 35.2% of visits and 19.5% of injections
No SR group: LLR rate: 8.9% of visits and 5.3% of injections (P < .001 each).
Conclusions: Patients with increased frequency of LLR may have increased risk for future SR .
retrospective review of a large, multi-center, allergy practice group’s database comparing the frequency of large local reactions, defined as ≥ 25 mm, in patients who had experienced systemic reactions with age, sex and sensitivity- matched controls who had not had allergen immunotherapy systemic reactions found the rate of large local reactions was three times higher amongst the 271 patients who had subsequently experienced a systemic reaction compared to those who had never experienced a systemic reaction: patients who had experienced systemic reactions had 1573 large local reactions in 4460 visits (i.e. 35.2% of visits) and 8081 injections (i.e. 19.5% of injections) compared with 1388 large local reactions in 15,540 visits (8.9% per visit) and 26,259 injections (5.3% per injection) in the matched control group without systemic reactions. P<0.001 (Fisher’s exact test). Individual large local reactions were not predictive of future systemic reactions but large local reactions preceded systemic reactions in approximately one-third of the systemic reactions. These findings suggest that individuals with a greater frequency of large local reactions may be a greater risk for systemic reaction. Prospective studies investigating the sensitivity and specificity of large local reactions and the impact of immunotherapy protocol modifications based on them are needed.
new reference Roy, Sitesh Increased Frequency of Large Local Reactions in Patients Who Experience Systemic Reactions on Allergen Immunotherapy
University of Mississippi Medical Center. Pro Con Debate ACAAI 2005 Annual Meeting
Roy et al., Ann Allergy Asthma Immunol 2007; 99: 82-6.

6. Subcutaneous Immunotherapy Systemic Reactions
SCIT SR rate varies greatly depending on several factors: allergen dose, extract type , induction schedule, premeditation, extract type, 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%).
symptoms
reported included pruritic eyes, nose, or pharynx(46%);
worsening cough (26%); sensation of difficulty swallowing
(20%); worsening nasal congestion (15%); rhinorrhea (13%);
chest tightness or shortness of breath (11%); generalized
pruritus (11%); sneezing (9%); wheeze (4%); and urticaria
(2%). No
Cox L, et al J Allergy Clin Immunol. 2010;125(3):569-74
Phillips JF, Lockey RF, et al Systemic reactions to subcutaneous allergen immunotherapy and the response to epinephrine. Allergy Asthma Proc. 2011;32(4):

7. WAO Subcutaneous Immunotherapy Systemic Reaction Grading Systems
5 Grades: based on organ system involved and severity.
Organ systems are defined as:
Cutaneous, conjunctival, upper respiratory,
Lower respiratory, gastrointestinal, cardiovascular and other.
Grade 1: single organ system such as cutaneous, conjunctival, upper respiratory, but not asthma, gastrointestinal or cardiovascular
Grade 2 & 3. Symptoms from >1 organ system or asthma, gastrointestinal, cardiovascular
Grade 4: Respiratory failure, hypotension ±loss of consciousness
The Grade is determined by the physician’s clinical judgment after the event is over.
Endorsed by AAAAI, ACAAI, the Latin American Society of Allergy and Immunology, the Asia
Pacific Association of Allergy, Asthma and Clinical Immunology,

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

9. The final reaction grade will not be determined until the event is over, regardless of the medication administered.
The final report should include the first symptom(s)/sign(s) and the time of onset after the SCIT injection and
A suffix that denotes if and when epinephrine is or is not administered in relationship to symptom(s)/sign(s) of the SR:
≤ 5 minutes;
>5 minutes to ≤10 minutes;
>10 to ≤ 20 minutes;
>20 minutes;
epinephrine not administered.

10. Excel Tracking Log for SR Grading & Treatment
PATIENT TRACKING LOG FOR SYSTEMIC REACTIONS TO ALLERGEN INJECTIONS
PAGE 2
WAO Subcutaneous Immunotherapy Systemic Reaction Grading System
EPI GIVEN
TREATMENT GIVEN
PATIENT ID NUMBER
DATE
Grade1
Grade 2
Grade 3
Grade 4
First symptom(s)
TIME OF ONSET AFTER INJECTION (MIN)
YES NO
TOTAL EPI DOSE (MG) IM
SUB-Q
≤ 5 MINS
>5- ≤10 MINS
>10-≤20 MINS
>20 MIN
Comments
JF3001
01//6/09 x
Urticaria 90
patient did not report the reaction until the following day.
MW678
0/2/19/09
Nasal 20
0.3
symptoms resoved within 10 minutes of epinephrine
SF76543
4/15/2009 15
cough,and wheezing 5 minutes later, given neb albuterol
AP36490
6/2/2009
Asthma 25
also given albuterol via neb
Cox L, Larenas-Linnemann D, Lockey RF, Passalacqua G. Speaking the same language: The World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System. J Allergy Clin Immunol. 2010;125(3):569-74, 74 e1-74 e7.

11. Worse Case Scenario Subcutaneous Immunotherapy Fatalities
3 surveys of AAAAI members on immunotherapy fatalities spanning time period between

12. 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
WAO Grade 4 reactions:
2 occurred within seconds & 10 minutes
1 RTC at 45minutes with a Grade
symptoms
reported included pruritic eyes, nose, or pharynx(46%);
worsening cough (26%); sensation of difficulty swallowing
(20%); worsening nasal congestion (15%); rhinorrhea (13%);
chest tightness or shortness of breath (11%); generalized
pruritus (11%); sneezing (9%); wheeze (4%); and urticaria
(2%). No
Cox L, et al J Allergy Clin Immunol. 2010;125(3):569-74
Tinkleman et al, JAllergy Clin Immunol. 1995;95 3 Phillips JF, Lockey RF, et al. 2011;32(4):

13. Timing of SCIT Systemic Reactions & Potential Risk Factors
7-years retrospective study to determine whether a pattern of greater STR is associated with elevated risk for systemic reaction.
Results: 20 patients had 46 SR in ,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: , 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.

14. AAAAI/ACAAI Surveillance Study of SCIT Safety: Time of Onset and Treatment of Systemic Reactions
In 3 years, no fatalities reported by ~806 physicians (representing 1922 SCIT prescribers & 8.1 million injection visits/year)
Of 222 (35% respondents) providing time of onset and epinephrine data on a total of 2,117 SRs:
Epinephrine was administered to most (77%) but not all SRs beginning within 30-minutes, including:
70% of Grade 1, 93% of Grade 2, 93% of Grade 3 SRs.
Delayed SR: 289 (13.7%) SR 289 occurred after 30 minutes
9 (13%) of delayed SR were Grade 3
Bernstein DI, Epstein T. Systemic reactions to subcutaneous allergen immunotherapy. Immunology and Allergy Clinics of North America. 2011;31(2):241-9

15. AAAAI/ACAAI Surveillance Study of SCIT Safety: Time of Onset and Grade
Per injection SR rate & number (%) practices reporting1
Grade 1 mild SR:
1 per 1,287 (.07% injection visits)
613 (76%) practices
Grade 2 moderate SR:
1 per 4,166 (.02% injection visits)
436 (54%) practices
Grade 3 severe SR:
1 per 30,566 (.003%)
144 (18%) practices
Practices reporting Grade 3 vs. 1 only were more likely to prescribe epinephrine autoinjectors, check patient identifiers prior to injection, and prescribe routine premedication & higher HDM doses.2
74%
23% 3%
1.Bernstein et al, Ann Allergy Asthma Immunol 2010;104:530-5.
2.Epstein et al, AAAAI/ACAAI Surveillance Study of SCIT(Year 2): Time of Onset and Treatment of SR (Abstract). JACI 2011.

16. AAAAI/ACAAI IT Safety Survey July 2010-July 2011
Response rates were down with 518 respondents representing 1,135 prescribers in (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

17. Biphasic Systemic Reactions
Summary Statement 35: Biphasic immunotherapy reactions, defined as resolution of the initial reaction with recurrence 2 to 24 hours, were reported in up to 23% of patients, who experienced a SR after SCIT in one study. Biphasic reactions were typically less severe than the initial reaction. C
2 prospective studies found 10%1 and 23%2 of IT SRs were biphasic
No specific symptoms during the initial reaction predicted a biphasic reaction.
Biphasic reactors more likely to be female , older and require >1 dose of epinephrine during initial SR
Biphasic reactions were typically less severe than the initial reaction and none required additional epinephrine
Confino-Cohen et al, Ann Allergy Asthma Immunol 2010;104:73-8.
Scranton et al, J Allergy Clin Immunol 2009;123:493-8.

18. 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.
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.

19. Accelerated Immunotherapy Schedules , Premedication and Medications to be Used with Caution

20. Advantages & Disadvantages of Accelerated Immunotherapy Schedules*
*Cox L. Advantages & disadvantages of accelerated immunotherapy schedules. J Allergy Clin Immunol 2008; 122:

21. Subcutaneous Rush Schedule
RIT incremental doses of allergen at intervals varying between 15 and 60 minutes over 1 to 3 days
Aeroallergen RIT schedules can be associated with greater risk of SR, premedication appears to reduce the risk (27% in premed vs. 73% in placebo premed group1)
The most accelerated schedule for inhalant allergens: 7 injections in 4 hours. Regimen includes 4 drug premedication: prednisone, LTR, AH and H2-blocker. SR occurred in 38% of patients; 1 severe systolic BP = 50 mm Hg
72% after last dose
16% after next to last
Remainder 3rd to last
1. Portnoy et al., Ann Allergy 1994;73:409-18
2. Harvey et al Ann Allergy Asthma Immunol. 2004;92(4):414-9.

22. Subcutaneous Rush Schedule
Ultrarush stinging insect protocols achieve the maintenance dose in 2.5 to 4 hours
RIT for administration of Hymenoptera have not been associated with a similar high incidence of systemic reactions.
Conflicting data on safety of fire ant (FA) RIT without premedication
1-day FA RIT without premedication reported 24.3% of the 37 patients experienced SR most being urticaria and pruritus
“Further studies are needed to clarify the risk of fire ant rush immunotherapy, and premedication might be considered.” (from the 2011 Allergen Immunotherapy Practice Parameter 3rd Update)
1. Tankersley J Allergy Clin Immunol. 2002;109(3):
2. Dietrich et al, Ann Allergy Asthma Immunol. 2009;103(6):535-6 .

23. Subcutaneous Cluster Schedule
Cluster entails administering several injections at increasing doses (generally 2-3 per visit) sequentially in a single day of treatment on nonconsecutive days.
Cluster schedule associated with the same or a slightly increased frequency of SRs compared with conventional schedules.
Example of a 8 visit 18 injection schedule in the ITPP
Cox L, Li J, Lockey R, Nelson H. Allergen immunotherapy: A practice parameter second update. JACI 2007;120:S25-S85.

24. Studies Comparing Cluster and Conventional Immunotherapy Schedule
DBPC study of 239 pts with dust mite AR ± asthma comparing 6-week with a 12-week conventional schedule found:1
No differences between the 2 schedules in terms of AEs
Improved clinical and objective parameters in the cluster 6 weeks before conventional group
Randomized study of 96 patients with dust mite AR comparing 6 week cluster with 14 week conventional found:
Cluster reduced time to maintenance dose by 57%.
No differences in SRs compared with conventional schedule.2
1. Taber et al., J Allergy Clin Immunol 2005; 116:109-18
2. Zhang et al., Int Arch Allergy Immunol 2009;148:161-9.

25. Systemic reactions with aeroallergen cluster immunotherapy in a clinical practice
Methods: A retrospective, observational review in a large, multicenter group regarding cluster IT safety
Maintenance dose based on AIPP guidelines, most premedicated
Results: Data from 441 cluster patients. 48 patients (10.9%) experienced SRs
Based on the WAO SCIT SR Grading System,
18 grade 1 reactions (38.3%),
23 grade 2 reactions (48.9%),
5 grade 3 reactions (10.6%),
Compared with clinics conventional IT during 2-yr period with 12,963 receiving SIT: SR rate 0.043% of IT visits and 2.2% of patients
BACKGROUND: Subcutaneous allergen-specific immunotherapy is a proven, highly effective treatment for immunoglobulin E-mediated diseases. Despite its proven benefits, only a small percentage of patients with allergic disease use immunotherapy, in part because of the inconvenience associated with treatment. Cluster allergen immunotherapy may offer patients a more convenient treatment option but is prescribed infrequently because of the perception that accelerated immunotherapy buildup leads a higher rate of systemic reactions. OBJECTIVE: To examine the safety of cluster immunotherapy and identify risk factors for systemic reactions during cluster buildup. METHODS: A retrospective, observational review in a large, multicenter allergy practice group was conducted for patients receiving cluster immunotherapy between May 2008 and October RESULTS: Data from 441 patients receiving cluster immunotherapy were collected. Forty-eight patients (10.9%) experienced systemic reactions. Based on the World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System, 18 grade 1 reactions (38.3%), 23 grade 2 reactions (48.9%), 5 grade 3 reactions (10.6%), 1 grade 4 reaction (2.1%), and no grade 5 reactions were seen. Risk factors for a systemic reaction included: female sex, physician diagnosis of asthma, age 21 to 40 years, and inclusion of certain allergens in the immunotherapy vaccine. CONCLUSIONS: Cluster immunotherapy allows patients to reach their immunotherapy maintenance dose more rapidly and may lead to more rapid symptomatic improvement. However, the 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):

26. 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.
BACKGROUND: Subcutaneous allergen-specific immunotherapy is a proven, highly effective treatment for immunoglobulin E-mediated diseases. Despite its proven benefits, only a small percentage of patients with allergic disease use immunotherapy, in part because of the inconvenience associated with treatment. Cluster allergen immunotherapy may offer patients a more convenient treatment option but is prescribed infrequently because of the perception that accelerated immunotherapy buildup leads a higher rate of systemic reactions. OBJECTIVE: To examine the safety of cluster immunotherapy and identify risk factors for systemic reactions during cluster buildup. METHODS: A retrospective, observational review in a large, multicenter allergy practice group was conducted for patients receiving cluster immunotherapy between May 2008 and October RESULTS: Data from 441 patients receiving cluster immunotherapy were collected. Forty-eight patients (10.9%) experienced systemic reactions. Based on the World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System, 18 grade 1 reactions (38.3%), 23 grade 2 reactions (48.9%), 5 grade 3 reactions (10.6%), 1 grade 4 reaction (2.1%), and no grade 5 reactions were seen. Risk factors for a systemic reaction included: female sex, physician diagnosis of asthma, age 21 to 40 years, and inclusion of certain allergens in the immunotherapy vaccine. CONCLUSIONS: Cluster immunotherapy allows patients to reach their immunotherapy maintenance dose more rapidly and may lead to more rapid symptomatic improvement. However, the 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):

27. Systemic tolerability of SCIT with IR– standardized allergen extracts administered using clustered regimens
Methods: Retrospective, observational, multicenter study in 1,147 patients who were treated with one of 9 cluster regimen
Results: 39 patients (3.4%) experienced 42 SRs (0.6% of doses). observed a higher risk of SRs in patients who received an initial dose higher than 0.3 index of reactivity (IR); only
Only 2 reactions occurred after initial dose both with 0.4 IR. Remainder never with a dose lower than 0.35 IR.
Conclusions: Clustered regimens with IR-standardized extracts are an alternative to classic immunotherapy initial dose no greater than 0.35 IR to minimize the incidence of SRs.
Serrano et al, Ann Allergy Asthma Immunol. 2009;102(3):

28. Measures to Improve Safety Premedication
Antihistamines
Studies with RIT & cluster suggest decreased incidence of local and SRs.
Conventional IT:
One DBPC study found premedication with fexofenadine reduced # of severe SRs, ↑ number of pts who reached TMD &↓ time to TMD1
Leukotriene receptor antagonist
Anecdotal reports of reductions in SR rates . One DBPC study demonstrated ↓ LLR during venom RIT with moneleukast2
1.Ohashi et al, Ann Allergy Asthma Immunol 2006; 96
2. Wohrl et al., Int Arch Allergy Immunol 2007;144:137-42

29. Omalizumab Premedication and Allergen Immunotherapy
Summary Statement 58: Omalizumab pretreatment has been shown to improve the safety and tolerability of cluster and rush immunotherapy schedules in patients with moderate-persistent asthma and allergic rhinitis, respectively. Additionally, omalizumab used in combination with immunotherapy has been shown to be effective in improving symptom scores compared to immunotherapy alone. A
Cox L, et al. Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol. 2011;127(1 Suppl):S1-55.

30. Effect of pretreatment with omalizumab on the tolerability of SIT in allergic asthma
Massanari et al, J Allergy Clin Immunol. 2010;125(2):383-9

31. Severity of First Systemic Allergic Reaction
Patients who experienced SR: omalizumab 13.5%, placebo 26.2% P= 0.017
N= N=32
Massanari et al, J Allergy Clin Immunol. 2010;125(2):383-9

32. β-adrenergic blocking agents and allergen Immunotherapy
Summary Statement 37: Exposure to β-adrenergic blocking agents is a risk factor for more serious and treatment-resistant anaphylaxis.  Concomitant use of β-blockers and allergen immunotherapy should be carefully considered from an individualized risk/benefit standpoint, and incorporate patient preferences in the medical decision-making process. C
Cardioselective β-blockers, which mainly affect β1 receptors, are less likely to promote bronchospasm than non-selective β-blockers….
Unusually severe anaphylaxis in patients taking ophthalmic and cardioselective β-blockers has been described for this reason, absence of increased β-blocker risk in association with either ophthalmic or β-blockers in patients receiving AIT cannot be assumed.
Cox L, et al. Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol. 2011;127(1 Suppl):S1-55.

33. ACE inhibitors & Venom Immunotherapy
Summary Statement 40: .
ACE inhibitors have been associated with greater risk for more severe reaction from VIT as well as field stings ACE inhibitor discontinuation should be considered for patients receiving VIT.
Concurrent administration of VIT and an ACE inhibitor is warranted in selected cases in which no equally efficacious alternative for an ACE inhibitor exists, and this is judged to be favorable from an individualized risk/benefit standpoint and consideration of patient preferences.
No evidence exists that angiotensin receptor blockers are associated with greater risk for anaphylaxis from allergen immunotherapy. C
Cox L, et al. Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol. 2011;127(1 Suppl):S1-55.

34. ACE Inhibitors Associated with More Severe but not More Frequent Venom Anaphylaxis
Retrospective review to evaluate frequency VIT or field sting SRs in 79 pts on angiotensin-converting enzyme inhibitors(ACE-I) did not find an increase SR frequency1
Cases of anaphylaxis/severe anaphylaxis in pts receiving VIT while on ACE Inhibitors, then none when withheld, with recurrence when ACE Inhibitor restarted.1 ,2
A large multi-center study found that ACE inhibitors were associated with increased risk for more severe anaphylaxis after venom field sting.3
These data provide support for the contention that ACE inhibitor use is not associated with increased SR frequency; however, greater risk for more serious reaction may still exist.
White KM, England RW. Ann Allergy Asthma Immunol 2008; 101:
Tunon-de-Lara et al, Lancet 1992;340:908
Ober et al, J Allergy Clin Immunol 2003;112:1008-9
Ruëff et al, J Allergy Clin Immunol 2009;124:

35. Measurement of Baseline Tryptase in Patients with Moderate-Severe Venom Anaphylaxis
Summary Statement 10b: Measurement of baseline serum tryptase level is recommended in patients with moderate or severe anaphylactic reactions to stings because its predictive value is useful regardless of the decision about VIT. Elevated tryptase is associated with more frequent and more severe anaphylactic reactions to stings, as well as greater failure rates with VIT and greater relapse rates after stopping VIT.B
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.

36. 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 but need in FA RIT unclear
Caution with ACE- inhibitor & beta-blockers including β1 -selective

37. 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

38. 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)

39. SLIT Safety in Published Literature
No reports of SLIT-related fatalities to date in an estimated ___billion doses
Most AE are local and occur in the beginning of treatment
Dose-response relationship with AEs in some studies
No apparent relationship with updosing schedule and AEs
Several large (>400 patients) grass-pollen tablet studies in adults & children demonstrate good safety profile with no updosing
Few reported cases of anaphylaxis (at least 6 )

40. Reported Rates of Adverse Events in Post-marketing Surveys
Author,
year N
pts
Age range
Follow- Up
Total AE % of
Patients
Total AE/1000
Doses
Local AE
% of patients
Di Rienzo, 1999
268
2-15
3 years
3 %*
0.083* 7%
Lombardi, 2001
198
18-65
5.5 %
0.5
1.5%
Pajno, 2003
354
5-15
3-4 years
6 %
0.15
Not stated
Fiocchi, 2005 65
3-7
1 year
15% 6%
Drachenberg, 2004
159
6-60
< 1 year
6.3% 5%
Agostinis, 2005 36
3-5
2 years
5 %
0.07
Di Rienzo, 2005
128
5. 6%
0.2
Rodriguez, 2008 43
8-20
11.6%*
0.3
46%
Agostinis, 2008
433
3-18
41%
4.4
32%
Lombardi, 2008
16-59
63%
6.5
* including systemic side effects only
Passalacqua et al, Grading side effects of sublingual immunotherapy speaking the same language in preparation

41. Characteristics Of The Slit-induced Anaphylaxis Reported In Literature
Author, year
Sex (age)
Allergen (producer)
Phase
Onset
Description
Epinephrine
De Groot, 2009
M (13)
Grass (Grazax, ALK-Abellò)
First dose
15 min
Generalized urticaria, swelling of tongue NO
F (27)
5 min
Abdominal cramps, asthma, generalized itching, hypotension
YES
Blazowski, 2008
F (16)
HDM (Staloral, Stallergenes)
Maintenance
overdose (60 drops)
10 min
Hypotension-collapse, flushing, urticaria
Eifan, 2008
F (11)
dust mite + grass pollen mix (Stallergenes)
Maintenance.
3 min
Abdominal pain, chest pain, fever, nausea
Not specified
Dunski, 2006
F (31)
Alternaria, cat, dog
grass, ragweed, (Greer)
2nd day of updosing
Angioedema, dizziness, dyspnea, generalized itching
Antico, 2006
F (36)
Latex
End of
rush buildup
Asthma, generalized urticaria
Passalacqua et al, Grading side effects of sublingual immunotherapy speaking the same language in preparation

42. 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 1st 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.
de Groot H, Bijl A. Anaphylactic reaction after the first dose of sublingual immunotherapy with grass pollen tablet. Allergy 2009; 64:963-4.

43. SLIT-Anaphylaxis: are there identifiable risk factors?
Risk factors in these cases? dose, gap in treatment, history of previous SR, updosing phase, multi-allergen treatment, delay in epinephrine, height of season, asthma????
Multiallergen SLIT Safety: Two postmarketing surveys (1 adult1, 1 pediatrics2) found no difference in safety of between single allergen & multiple allergen SLIT.
Previous SR: prospective study of 43 pts receiving SLIT : 3/5 pts with SLIT SR had previous SCIT SRs3
Lombardi C Allergy 2008; 63:375-6
Agostinis F ,Allergy 2008; 63:1637-9
Rodriguez-Perez N Ann Allergy Asthma Immunol 2008; 101:304-10

44. Most Adverse Reactions Occur During Beginning of SLIT Treatment
Dosing Range 5 to 200 mcg Phl p 5:
Most AEs occurred within the 1st few weeks then declined
Pattern similar to other studies
Higher doses=more AEs
Kleine-Tebbe Allergy 2006; 61:

45. Comparison of 2 vs. 4 Month Pre & Co-seasonal Grass-pollen Tablet in an Intermittent 3-Year Treatment Regimen
Didier et al, J Allergy Clin Immunol. 2011;128(3):

46. Full analysis set of patients over 4 evaluation seasons
Randomized patients = 633
Placebo = 219
205 (94%)
300IR (2M) = 207
188 (91%)
300IR (4M) = 207
year 1
(2007)
year 1
(2007)
188 (91%)
172 (79%)
155 (75%)
160 (77%)
year 2
(2008)
year 2
(2008)
year 3
(2009)
year 3
(2009)
165 (75%)
147 (71%)
149 (72%)
A high-quality study (few protocol deviations).
155 (71%)
year 4
(2010)
137 (66%)
year 4
(2010)
143 (69%)
Didier et al, J Allergy Clin Immunol. 2011;128(3):559-66 46

47. Treatment Emergent AEs (≥ 5% in any treatment group)
Compared with season 1, seasons 2 and 3 showed a progressive decrease in the:
Incidence of AE
Intensity of AE
Didier et al, J Allergy Clin Immunol. 2011;128(3):559-66 47

48. Description of the local side effects related to SLIT Using MeDRA Terminology 
MeDRA PREFERRED
TERM
MeDRA
CODE
Low level term (LLT)
MOUTH/
EAR
Altered taste perception
Dysgeusia
Taste alteration
Itching of lips
Oral pruritus
Itching mouth
Swelling of lips
Lip swelling
Swelling lips
Itching of the oral mucosa
Swelling of the oral mucosa
Oedema mucosal
Mucosal swelling
Itching of the ears
Ear pruritus
Swelling of the tongue
Swollen tongue
Tongue swelling non-specific
Glossodynia
Mouth ulcer
Mouth  ulceration
Tongue ulcer
Tongue ulceration
Throat irritation
Uvular oedema
Pharyngeal oedema
UPPER
GASTRO
INTESTINAL
Nausea
Stomach-ache
Abdominal pain upper
Stomach ache
Vomiting
LOWER
Abdominal pain
Diarrhea
Diarrhoea
Passalacqua et al, Grading side effects of sublingual immunotherapy speaking the same language in preparation

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

50. EAACI Immunotherapy Task Force Recommendations
“The scientific documentation for treatment schedules and dose modifications is limited. For routine treatment following the guidelines from the manufacturers is sensible.
• The administration of SLIT must be postponed in the following circumstances:
– In the presence of oro-pharyngeal infection.
– In the case of major dental surgery.
– Acute gastroenteritis.
– Exacerbation of the asthma.
– PEFR <80% of personal best value.
– Simultaneous administration of viral vaccines.”
Alvarez-Cuesta et al. Standards for practical allergen-specific immunotherapy. Allergy 2006; 61 Suppl 82:1-20.

51. Sublingual Immunotherapy Safety Summary
Specific instructions should be provided regarding the management of AE, unplanned interruptions in treatment and situations when SLIT should be withheld.
SLIT should only be prescribed by allergy-trained physicians
Canonica GW, Bousquet J, Casale T, Lockey RF, Baena-Cagnani CE, Pawankar R, et al. Sub-lingual immunotherapy: World Allergy Organization Position Paper Allergy. 2009;64 Suppl 91:1-59.

52. Sublingual Immunotherapy Safety Summary
WAO SLIT Position Paper Paris 2009
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

53. 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 Allergy. 2009;64 Suppl 91:1-59.

54. 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 Allergy. 2009;64 Suppl 91:1-59.

55. Novel Immunotherapy Formulations And Routes: Looking Toward The Future

56. Adjuvants: CpG and MPL
TOLAMBA: ISS of DNA CpG motif covalently linked to Amb a 1
TLR9 agonist: shifts immune response toward TH1
Protocol: 6 injections-highest dose 30 mcg Amb a 1
PC trial of 738 subjects with AR reported that treatment “was well tolerated in all groups” and no TOLAMBA-related SAEs2
Pollinex® Quattro/MATA MPL + modified allergen
TLR4 agonist: shown to induce TH1 cytokines
Protocol: 4 injections; highest dose 24 mcg of Php p 1
One-year postmarketing surveillance of 1736 pt, given injections, SR were reported by 1.6% of the patients.14 patients reported severe reactions but there no instances of anaphylactic shock.2
DBPC study of 1028 pts found MPL (514 pts) was “well tolerated”
1. . Bernstein et al., JACI 2007;119:S78-S9 2. Drachenberg et al., Int Rev Allergol Clin Immunol 2002;8: DuBuske Allergy Asthma Proc. 2011;32(3):

57. Nasal Immunotherapy
Nasal: associated with significant local SEs. Highest ‘dropout’ rate in study comparing compliance between SCIT, SLIT & LNIT (43.9% in 1st yr): unpleasant most sited reason(56.6%)
Pajno et al, JACI 2005;116:1380-1

58. Reasons for discontinuation of nasal IT
Pajno et al, JACI 2005;116:1380-1

59. Intralymphatic Immunotherapy
Intralymphatic (ILIT): non-controlled study was conducted with 165 grass-pollen allergic subjects comparing 3 injections of grass allergen extract into the inguinal lymph nodes at 4 week intervals to 3 years SCIT 3
Results: The total extract dose was more than 1000-fold less with ILIT.
Systemic reactions were less frequent, but nasal tolerance to allergen increased more rapidly with ILIT.
After three years, there were no clinical differences in outcomes between the two treatments.
Senti et al, Proc Natl Acad Sci U S A 2008;105: .

60. Less Pain Associated with Intralymphatic Immunotherapy than Venipuncture
Senti et al, Proc Natl Acad Sci U S A 2008;105: .

61. Epicutaneous Immunotherapy
Epicutaneous (EPIT): DPPC study of 37 pts treated with epicutaneous patch with grass pollen extract applied once weekly for 12 weeks for 48 hours each time beginning 4 weeks prior to and through grass pollen season. Site tape stripped prior to administration
Subjects receiving EPIT reported fewer symptoms than the placebo treated subjects for both the 2006 and 2007 grass pollen seasons.
The major adverse effect was an eczematous reaction at the application sites.
Senti et. al, JACI 2009;124:

62. Epicutaneous Immunotherapy 2nd Study
DBPC dose response study of 132 pts 6 weekly patches for 8 hours .
Higher doses associated with more AE –primarily, eczema wheal, erythema or pruritus
Occurrence of LRs decreased with each patch application
11 pts (8.3%) stopped treatment because of SR (WAO Grade 1 or 2), all cutaneous and 4 also had with cough, rhinitis or vertigo
Epicutaneous Allergen-specific Immunotherapy Ameliorates Grass-Pollen Induced Rhinoconjunctivitis: JACI in press

63. Oral peanut immunotherapy in children with peanut anaphylaxis
Study: 23 pts underwent rush peanut oral IT followed by build-up with aim of 500 mg =1 peanut
22 patients completed rush phase: adverse reactions were frequent: 25 / 317 total objective allergic symptoms. GI e.g., emesis and diarrhea followed by skin e.g., urticaria, angioedema, and flush were the most common
Blumchen et alJ Allergy Clin Immunol. 2010;126(1):83-91

64. Oral peanut immunotherapy in children with peanut anaphylaxis
4 drop-outs due to AE-all had mild-moderate asthma
Adverse reactions no less frequent in the long-term build-up,/maintenance than rush
1.3% doses resulted in a pulmonary AE
Blumchen et alJ Allergy Clin Immunol. 2010;126(1):83-91

65. The Risk of Not Receiving SCIT Compared with ‘Usual Treatment’: IHD, Autoimmunity & Mortality
Objective: To investigate the association of SCIT with the incidence of autoimmune disease ischemic heart disease (IHD) and all-cause mortality.
Methods: All Danish citizens , age 18 by 1997 ,without other known diseases followed through central registries on medications and hospital admissions. Study period:
Compared persons receiving SCIT and persons receiving conventional allergy treatment (CAT; nasal steroids or oral antihistamines) with regard to mortality and development of autoimmune diseases, acute myocardial infarction (AMI), and IHD.
ACKGROUND: Subcutaneous allergen-specific immunotherapy (SCIT) is a well-documented treatment of IgE-mediated allergic disease. Little is known about potential effects of SCIT on the risk of other chronic immune-related diseases. Over the years, a few casuistic reports have caused concern that SCIT might act as a trigger of autoimmune disease. OBJECTIVE: We aimed to investigate the association of SCIT with the incidence of autoimmune disease and ischemic heart disease (IHD), as well as all-cause mortality. METHODS: All Danish citizens without other known diseases were linked and followed through central registries on medications and hospital admissions. Persons receiving SCIT and persons receiving conventional allergy treatment (CAT; nasal steroids or oral antihistamines) were compared with regard to mortality and development of autoimmune diseases, acute myocardial infarction (AMI), and IHD. Cox regression (survival analysis) with age as the underlying time scale was used to estimate relative risks (hazard ratios [HRs] with 95% CIs) associated with SCIT compared with CAT adjusted for age, sex, vocational status, and income. RESULTS: During the 10-year study period ( ), a total of 18,841 and 428,484 persons were followed in the SCIT and CAT groups, respectively. Receiving SCIT was associated with lower mortality (HR, 0.71; 95% CI, ) and lower incidence of AMI (HR, 0.70; 95% CI, ), IHD (HR, 0.88; 95% CI, ), and autoimmune disease (HR, 0.86; 95% CI, ). CONCLUSION: In this registry-based observational study, receiving SCIT compared with CAT was associated with lower risk of autoimmune disease and AMI, as well as decreased all-cause mortality.
Linneberg A, et al, Association of subcutaneous allergen-specific immunotherapy with incidence of autoimmune disease, ischemic heart disease, and mortality. J Allergy Clin Immunol in press

66. Lower Risk : IHD, Autoimmunity & All-cause Mortality with SCIT Compared with CAT
Results: During the 10-yr period, 18,841 SCIT and 428,484 CAT.
SCIT was associated with:
lower mortality (HR, 0.71; 95% CI, ) and
lower incidence of AMI (HR, 0.70; 95% CI, ),
IHD (HR, 0.88; 95% CI, )
autoimmune disease (HR, 0.86; 95% CI, ).
Conclusion: In this registry-based observational study, receiving SCIT compared with CAT was associated with lower risk of autoimmune disease and AMI, as well as decreased all-cause mortality.
ACKGROUND: Subcutaneous allergen-specific immunotherapy (SCIT) is a well-documented treatment of IgE-mediated allergic disease. Little is known about potential effects of SCIT on the risk of other chronic immune-related diseases. Over the years, a few casuistic reports have caused concern that SCIT might act as a trigger of autoimmune disease. OBJECTIVE: We aimed to investigate the association of SCIT with the incidence of autoimmune disease and ischemic heart disease (IHD), as well as all-cause mortality. METHODS: All Danish citizens without other known diseases were linked and followed through central registries on medications and hospital admissions. Persons receiving SCIT and persons receiving conventional allergy treatment (CAT; nasal steroids or oral antihistamines) were compared with regard to mortality and development of autoimmune diseases, acute myocardial infarction (AMI), and IHD. Cox regression (survival analysis) with age as the underlying time scale was used to estimate relative risks (hazard ratios [HRs] with 95% CIs) associated with SCIT compared with CAT adjusted for age, sex, vocational status, and income. RESULTS: During the 10-year study period ( ), a total of 18,841 and 428,484 persons were followed in the SCIT and CAT groups, respectively. Receiving SCIT was associated with lower mortality (HR, 0.71; 95% CI, ) and lower incidence of AMI (HR, 0.70; 95% CI, ), IHD (HR, 0.88; 95% CI, ), and autoimmune disease (HR, 0.86; 95% CI, ). CONCLUSION: In this registry-based observational study, receiving SCIT compared with CAT was associated with lower risk of autoimmune disease and AMI, as well as decreased all-cause mortality.
Linneberg A, et al, J Allergy Clin Immunol in press

67. Immunotherapy Safety Take Home Points
SCIT safe but requires medical supervision
SLIT appears to have safer profile, home administration standard of care with appropriate patient education
Adjuvants offer ultra-short course with some systemic AE but administered
Nasal-significant local AEs
Epicutaneous skin AE common and some SR reported
Intralymphatic small study number but signifcant safety signal
Food oral IT: frequent AEs
WAO Grading System for Systemic Reactions and SLIT Local Reactions
..please use!!!!