Linda Cox, MD, FAAAAI, FACAAIAssociate Clinical Professor of Medicine Nova Southeastern UniversityFt. Lauderdale, Florida

Allergen Immunotherapy SafetyAllergen Immunotherapy Safety

Subcutaneous immunotherapySublingual Immunotherapy

Adverse reactions: types and incidence per published studies ,post marketing surveillance & surveysLessons learned from the literature: risk factorsWAO Grading system for SCIT/SLIT systemic reactions and SLIT local reactions

Other forms of immunotherapyOral immunotherapy (foods)Adjuvants/peptidesEpicutaneous/intralympahatic

Subcutaneous Immunotherapy Adverse Subcutaneous Immunotherapy Adverse ReactionsReactionsLocal SCIT reactions

Erythema, pruritus and swelling at the injection siteVery 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

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

Subcutaneous Immunotherapy Adverse Subcutaneous Immunotherapy Adverse ReactionsReactions

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;121:222-6. 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

Individuals with a greater frequency of LLR Individuals with a greater frequency of LLR may be a greater risk for SRmay 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 mmResults: 258 pts had 283 SRs in 108,621 injections

LLR rate 4 times higher in pts with SRs than pts with no SRsSR group: LLR rate: 35.2% of visits and 19.5% of injectionsNo 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 .

Roy et al., Ann Allergy Asthma Immunol 2007; 99: 82-6.

Subcutaneous Immunotherapy Systemic Subcutaneous Immunotherapy Systemic ReactionsReactionsSCIT 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%).

1. Cox L, et al J Allergy Clin Immunol. 2010;125(3):569-742. 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.

WAO Subcutaneous Immunotherapy Systemic WAO Subcutaneous Immunotherapy Systemic Reaction Grading SystemsReaction 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 cardiovascularGrade 2 & 3. Symptoms from >1 organ system or asthma, gastrointestinal, cardiovascularGrade 4: Respiratory failure, hypotension ±loss of consciousnessThe 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 AsiaPacific Association of Allergy, Asthma and Clinical Immunology,

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

The final reaction grade will not be determined until The final reaction grade will not be determined until the event is over, regardless of the medication the event is over, regardless of the medication

administered. 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:

a. ≤ 5 minutes; b. >5 minutes to ≤10 minutes; c. >10 to ≤ 20 minutes; d. >20 minutes;

z. epinephrine not administered.

PATIENT TRACKING LOG FOR SYSTEMIC REACTIONS TO ALLERGEN INJECTIONS PATIENT TRACKING LOG FOR SYSTEMIC REACTIONS TO ALLERGEN INJECTIONS

PAGE 2

WAO Subcutaneous Immunotherapy Systemic

Reaction Grading System EPI GIVEN

EPI GIVEN

TREATMENT GIVEN

PATIENT ID NUMBER DATE Grade1 Grade 2 Grade 3 Grade 4

First sympto

m(s)

PATIENT ID

NUMBER

TIME OF

ONSET AFTER INJECTI

ON (MIN)

YES NO

TOTAL EPI DOSE (MG)

IM SUB-Q

≤ 5 MINS

>5- ≤10 MINS

>10-

≤20 MINS

>20 MIN

Comments

JF300101//6/09 x

Urticaria JF3001 90 x

patient did not report the reaction until the following day.

MW6780/2/19/09 x Nasal MW678 20x 0.3x x

symptoms resoved within 10 minutes of epinephrine

SF765434/15/2009 x

Urticaria SF76543 15x 0.3x

cough,and wheezing 5 minutes later, given neb albuterol

AP364906/2/2

009 x Asthma AP36490 25x 0.3x 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.

Excel Tracking Log for SR Grading & Excel Tracking Log for SR Grading & TreatmentTreatment

3 surveys of AAAAI members on immunotherapy fatalities spanning time period between 1945-2001

Timing of SCIT Systemic ReactionsTiming 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 & EACCIMost 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 minutes1 RTC at 45minutes with a Grade 3 4

1. Cox L, et al J Allergy Clin Immunol. 2010;125(3):569-742. Tinkleman et al, JAllergy Clin Immunol. 1995;95 3 Phillips JF, Lockey RF, et al. 2011;32(4):288-94.

Timing of SCIT Systemic Reactions & Potential Risk Timing of SCIT Systemic Reactions & Potential Risk FactorsFactors

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 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.

AAAAI/ACAAI Surveillance Study of SCIT Safety: Time of AAAAI/ACAAI Surveillance Study of SCIT Safety: Time of Onset and Treatment of Systemic ReactionsOnset 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

AAAAI/ACAAI Surveillance Study of SCIT Safety: AAAAI/ACAAI Surveillance Study of SCIT Safety: Time of Onset and Grade 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

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.

74%

23%

3%

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

Biphasic Systemic ReactionsBiphasic Systemic ReactionsSummary 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 biphasicNo 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

171. Confino-Cohen et al, Ann Allergy Asthma Immunol 2010;104:73-8. 2. Scranton et al, J Allergy Clin Immunol 2009;123:493-8.

Wait Period & Delayed reactionsWait 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.

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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.

Advantages & Disadvantages of Accelerated Immunotherapy Schedules*

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

*

Subcutaneous Rush ScheduleSubcutaneous Rush ScheduleRIT 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 dose16% after next to lastRemainder 3rd to last

1. Portnoy et al., Ann Allergy 1994;73:409-182. Harvey et al Ann Allergy Asthma Immunol. 2004;92(4):414-9.

Subcutaneous Rush ScheduleSubcutaneous Rush ScheduleUltrarush stinging insect protocols achieve the maintenance dose in 2.5 to 4 hoursRIT 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 premedication1-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):556-62. 2. Dietrich et al, Ann Allergy Asthma Immunol. 2009;103(6):535-6.

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.

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 AEsImproved 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.

Methods: A retrospective, observational review in a large, multicenter group regarding cluster IT safety Maintenance dose based on AIPP guidelines, most premedicatedResults: Data from 441 cluster patients. 48 patients (10.9%) experienced SRsBased 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 patientsCopenhaver et al. Ann Allergy Asthma Immunol. 2011;107(5):441-7..

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..

Systemic tolerability of SCIT with IR– standardized allergen extracts administered using clustered regimens

Methods: Methods: Retrospective, observational, multicenter study in 1,147 Retrospective, observational, multicenter study in 1,147 patients who were treated patients who were treated with one of 9 cluster regimenResults: 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):247-52.

Measures to Improve Safety PremedicationMeasures to Improve Safety Premedication

AntihistaminesStudies 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; 962. Wohrl et al., Int Arch Allergy Immunol 2007;144:137-42

Omalizumab Premedication and Allergen Omalizumab Premedication and Allergen ImmunotherapyImmunotherapy

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.

Massanari et al, J Allergy Clin Immunol. 2010;125(2):383-9

Severity of First Systemic Allergic ReactionSeverity of First Systemic Allergic Reaction

7

26

26

0

24

2

0

5

10

15

20

25

30

Grade 1 (Skin) Grade 2 (GI) Grade 3(Resp)

Grade 4 (CV)

Nu

mb

er

of

Pa

tien

ts

Omalizumab PlaceboN=17 N=32

Patients who experienced SR: omalizumab 13.5%, placebo 26.2% P= 0.017

Massanari et al, J Allergy Clin Immunol. 2010;125(2):383-9

β-adrenergic blocking agents and allergen β-adrenergic blocking agents and allergen ImmunotherapyImmunotherapy

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.

ACE inhibitors & Venom ImmunotherapyACE 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.

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.

34

ACE Inhibitors Associated with More Severe but not More ACE Inhibitors Associated with More Severe but not More Frequent Venom Anaphylaxis Frequent Venom Anaphylaxis

1. White KM, England RW. Ann Allergy Asthma Immunol 2008; 101:426-30.2. Tunon-de-Lara et al, Lancet 1992;340:9083. Ober et al, J Allergy Clin Immunol 2003;112:1008-94. Ruëff et al, J Allergy Clin Immunol 2009;124:1047-54.

Measurement of Baseline Tryptase in Patients with Measurement of Baseline Tryptase in Patients with Moderate-Severe Venom AnaphylaxisModerate-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.

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 infrequentlyFatalities 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.

PremedicationReduces LR and SR with conventional & accelerated IT schedulesRecommended for aeroallergen RITDoes not appear to be needed for VIT but need in FA RIT unclear

Caution with ACE- inhibitor & beta-blockers including β1 -selective

Sublingual Immunotherapy Safety Sublingual Immunotherapy Safety

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

AAAAI/ACAAI JTF Summary of AAAAI/ACAAI JTF Summary of SLIT Adverse Events 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 fatalitiesOral-mucosal symptoms: affecting up to 75% of patientsSystemic 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 hospitalizedPost JTF report:4 cases of anaphylaxis in the published literature: 2 hospitalized and 1 with LOC (B/P 70/40)

SLIT Safety in Published LiteratureSLIT 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 )

* including systemic side effects only

Passalacqua et al, Grading side effects of sublingual immunotherapy speaking the same language. 2011 in preparation

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

De Groot, 2009

F (27) Grass (Grazax, ALK-Abellò)

First dose 5 min Abdominal cramps, asthma, generalized itching, hypotension

YES

Blazowski, 2008

F (16) HDM (Staloral, Stallergenes)

Maintenanceoverdose (60 drops)

10 min Hypotension-collapse, flushing, urticaria

YES

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, doggrass, ragweed, (Greer)

2nd day of updosing

5 min Angioedema, dizziness, dyspnea, generalized itching

NO

Antico, 2006 F (36) Latex End of rush buildup

10 min Asthma, generalized urticaria

Not specified

Passalacqua et al, Grading side effects of sublingual immunotherapy speaking the same language. 2011 in preparation

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 tablet24 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.

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

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

43

1. Lombardi C Allergy 2008; 63:375-6 2. Agostinis F ,Allergy 2008; 63:1637-9 3. Rodriguez-Perez N Ann Allergy Asthma Immunol 2008; 101:304-10

Most Adverse Reactions Occur During Beginning of SLIT Treatment

Most AEs occurred within the 1st few weeks then declinedPattern similar to other studiesHigher doses=more AEs

Kleine-Tebbe Allergy 2006; 61: 181-184

Dosing Range 5 to 200 mcg Phl p 5:

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):559-66. 45

Full analysis set of patients over 4 evaluation seasons

year 1(2007)

year 2(2008)

year 3(2009)

year 1(2007)

year 2(2008)

year 3(2009)

•Didier et al, J Allergy Clin Immunol. 2011;128(3):559-66

165 (75%)

172 (79%)

147 (71%)

300IR (4M) = 207

188 (91%)

155 (75%) 160 (77%)

149 (72%)

Randomized patients = 633

year 4(2010)

155 (71%) year 4(2010)

137 (66%) 143 (69%)

Compared with season 1, seasons 2 and 3 showed a progressive decrease in the:

•Incidence of AE •Intensity of AE

47

Didier et al, J Allergy Clin Immunol. 2011;128(3):559-66

Passalacqua et al, Grading side effects of sublingual immunotherapy speaking the same language. 2011 in preparation

LOCAL SIDE EFFECT MeDRA PREFERREDTERM

MeDRACODE

MeDRALow level term (LLT)

MOUTH/EAR

Altered taste perception Dysgeusia 10013911 Taste alteration

Itching of lips Oral pruritus 10052894 Itching mouth

Swelling of lips Lip swelling 10024570 Swelling lips

Itching of the oral mucosa Oral pruritus 10052894 Itching mouth

Swelling of the oral mucosa Oedema mucosal 10030111 Mucosal swelling

Itching of the ears Ear pruritus 10052138 Ear pruritus

Swelling of the tongue Swollen tongue 10042727 Tongue swelling non-specific

Glossodynia Glossodynia 10018388 Glossodynia

Mouth ulcer Mouth ulceration 10028034 Mouth ulcer

Tongue ulcer Tongue ulceration

10043991

Tongue ulceration

Throat irritation Throat irritation 10043521 Throat irritation

Uvular oedema Pharyngeal oedema 10034829 Pharyngeal oedema

UPPERGASTROINTESTINAL

Nausea Nausea 10028813 Nausea

Stomach-ache Abdominal pain upper 10000087 Stomach ache

Vomiting Vomiting 10047700 Vomiting

LOWER GASTROINTESTINAL

Abdominal pain Abdominal pain 10000081 Abdominal pain

Diarrhea Diarrhoea 10012735 Diarrhea

WAO Grading System for SLIT Local Reactions

Passalacqua et al, Grading side effects of sublingual immunotherapy speaking the same language. 2011 in preparation

Symptom/sign

Grade 1 – Mild Grade 2 – Moderate

Grade 3 - Severe

Unknown severity

Abdominal pain, Diarrhea Ear itching Pruritus/swelling of mouth, tongue or lip Nausea Throat irritation Uvular oedema Vomiting

● Not troublesome AND ● No symptomatic treatment required AND ● No discontinuation of SLIT because of local side effects

● Troublesome OR ● Requires symptomatic treatment AND ●No discontinuation of SLIT because of local side effects

Grade 2 AND

SLIT discontinued because of local side effects

The treatment is discontinued but there is no subjective and/or objective description of the severity from the patient/physician

Each local adverse event can be early (<30 minutes) or delayed

EAACI Immunotherapy Task Force EAACI Immunotherapy Task Force RecommendationsRecommendations

“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.

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

Sublingual Immunotherapy Safety Summary

SLIT appears to be better tolerated than SCITMajority of SLIT AE’s are oromucosal & occur during the beginning of treatmentA few cases of SLIT-related anaphylaxis have been reported but no fatalitiesRisk factors for the occurrence of SLIT SAE have not yet been established Proposed WAO system of for reporting SLIT adverse local reactionsWAO 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

The safety of SLIT in patients who have had SR with SCITThe safety of SLIT with multiple allergensInterruptions 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.

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.

Novel Immunotherapy Novel Immunotherapy Formulations And Routes: Formulations And Routes: Looking Toward The FutureLooking Toward The Future

TOLAMBA: ISS of DNA CpG motif covalently linked to Amb a 1TLR9 agonist: shifts immune response toward TH1Protocol: 6 injections-highest dose 30 mcg Amb a 1PC 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 allergenTLR4 agonist: shown to induce TH1 cytokinesProtocol: 4 injections; highest dose 24 mcg of Php p 1One-year postmarketing surveillance of 1736 pt, given 8512 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;8:219-23 3. DuBuske Allergy Asthma Proc. 2011;32(3):239-47.

Nasal ImmunotherapyNasal ImmunotherapyNasal: 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

Reasons for discontinuation of nasal ITReasons for discontinuation of nasal IT

Pajno et al, JACI 2005;116:1380-1 58

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;105:17908-12..

Less Pain Associated with Intralymphatic Immunotherapy than Venipuncture

Senti et al, Proc Natl Acad Sci U S A 2008;105:17908-12..

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 administrationSubjects 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;124:997-1002.

Epicutaneous Immunotherapy 2nd StudyDBPC dose response study of 132 pts 6 weekly patches for 8 hours . Higher doses associated with more AE –primarily, eczema wheal, erythema or pruritusOccurrence of LRs decreased with each patch application11 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

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

4 drop-outs due to AE-all had mild-moderate asthma Adverse reactions no less frequent in the long-term build-up,/maintenance than rush1.3% doses resulted in a pulmonary AE

Blumchen et alJ Allergy Clin Immunol. 2010;126(1):83-91

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:1997-2006.

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.

Linneberg A, et al, Association of subcutaneous allergen-specific immunotherapy with incidence of autoimmune disease, ischemic heart disease, and mortality. J Allergy Clin Immunol. 2011 in press

Results: During the 10-yr period, 18,841 SCIT and 428,484 CAT. SCIT was associated with:

lower mortality (HR, 0.71; 95% CI, 0.62-0.81) and lower incidence of AMI (HR, 0.70; 95% CI, 0.52-0.93), IHD (HR, 0.88; 95% CI, 0.73-1.05)autoimmune disease (HR, 0.86; 95% CI, 0.74-0.99).

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. 2011 in press

SCIT safe but requires medical supervisionSLIT appears to have safer profile, home administration standard of care with appropriate patient educationAdjuvants offer ultra-short course with some systemic AE but administered Nasal-significant local AEsEpicutaneous skin AE common and some SR reportedIntralymphatic small study number but signifcant safety signalFood oral IT: frequent AEsWAO Grading System for Systemic Reactions and SLIT Local Reactions ..please use!!!!