Understand the Difference between Local and Systemic Reactions

Michael S. Blaiss, MDClinical Professor of Pediatrics and Medicine

University of Tennessee Health Science Center Memphis, Tennessee

Allergen Immunotherapy ReactionsAllergen Immunotherapy Reactions

• Subcutaneous immunotherapy (SCIT)– Local

• Large Local• Biphasic

– Systemic

• Sublingual Immunotherapy (SLIT)– Local– Systemic

Subcutaneous Immunotherapy Adverse ReactionsSubcutaneous 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

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.

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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

Subcutaneous Immunotherapy Systemic Subcutaneous Immunotherapy Systemic ReactionsReactions• 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):569-742. 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.

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

Worse Case Scenario Subcutaneous Immunotherapy Fatalities

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 & 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):569-742. 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 FactorsTiming 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.

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

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.

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

Advantages & Disadvantages of Accelerated Immunotherapy Schedules*

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

*

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..

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 β1 -selective

Sublingual Immunotherapy Safety 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

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)

Treatment-Related Adverse Events in ≥5% of Subjects

Adult Studies Pediatric Studies

Treatment-RelatedAdverse Event, n (%)

Grass AIT(n=1060)

Placebo(n=1036)

Grass AIT(n=302)

Placebo(n=296)

Oral pruritus 409 (39%) 47 (5%) 107 (35%) 9 (3%)

Throat irritation 227 (21%) 26 (3%) 75 (25%) 7 (2%)

Ear pruritus 145 (14%) 10 (1%) 25 (8%) 1 (<1%)

Mouth edema 121 (11%) 6 (<1%) 23 (8%) 1 (<1%)

Oral paresthesia 86 (8%) 13 (1%) N/A N/A

Stomatitis* N/A N/A 26 (9%) 2 (1%)

Lip swelling N/A 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

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 Studies Pediatric Studies

Median Day of OnsetMedian Number of

Days Median Day of OnsetMedian Number of

Days

Adverse EventGrass 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 pruritus 1 1 8 2 1 1 5 1

Throat irritation 1 1 6 3 1 1 4 1

Ear pruritus 1 23 4 2 1 1 6 1

Mouth edema 5 1 30 1 8 2 17 1

Oral paresthesia 1 1 10 2 N/A N/A N/A N/A

Stomatitis* N/A N/A N/A N/A 1 53 2 1

Lip swelling N/A N/A N/A N/A 3 — 2 —

N/A=not applicable; incidence was <5%. *Indicates mild erythema, not lesions or infection.

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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.

20de Groot H, Bijl A. Anaphylactic reaction after the first dose of sublingual immunotherapy with grass pollen tablet. Allergy 2009; 64:963-4.

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

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

Sublingual Immunotherapy Safety: Unmet NeedsAnswered/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.

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.

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