Transcript old ppWAO 2011 IT safety

Linda Cox, MD, FAAAAI, FACAAI
Associate Clinical Professor of Medicine Nova
Southeastern University
Ft. Lauderdale, Florida
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
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;124:739-44 2.Coop et al, Ann Allergy Asthma Immunol. 2008;101(1):96100. 3. Tankersley MS. Curr Allergy Asthma Rep. 2011;11(2):115-214.
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;121:222-6. 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 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 .
Roy et al., Ann Allergy Asthma Immunol 2007; 99: 82-6.
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%).
1. Cox L, et al J Allergy Clin Immunol. 2010;125(3):569-74
2. Phillips JF, Lockey RF, et al Systemic reactions to subcutaneous allergen immunotherapy and the
response to epinephrine. Allergy Asthma Proc. 2011;32(4):288-94.
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,
Cox et al, J Allergy Clin Immunol 2010;125:569-74
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:
a.
b.
c.
d.
≤ 5 minutes;
>5 minutes to ≤10 minutes;
>10 to ≤ 20 minutes;
>20 minutes;
z.
epinephrine not administered.
Excel Tracking Log for SR Grading & Treatment
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 TREATMEN
GIVEN T GIVEN
TIME
OF
>10
TOTA
>5First
PATIENT ONSET
≤5
- >20
L EPI
SU
≤10
Grade 2 Grade 3 Grade 4 sympto
ID
AFTER YES NO
IM
MI
≤20 MI
DOSE
B-Q
MI
m(s)
NUMBER INJECTI
NS
MI N
(MG)
NS
ON
NS
(MIN)
PATIENT ID
DATE Grade1
NUMBER
JF3001
01//6
/09 x
Urticari
a
JF3001
90
MW678
0/2/1
9/09 x
Nasal
MW678
20x
0.3x
x
Urticari
a
SF76543
15x
0.3x
x
Asthma AP36490
25x
0.3x
SF76543
AP36490
4/15/
2009
6/2/2
009
x
x
Comments
patient did not report
the reaction until the
following day.
symptoms resoved
within 10 minutes of
epinephrine
cough,and wheezing 5
minutes later, given
neb albuterol
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.
Worse Case Scenario Subcutaneous Immunotherapy Fatalities
3 surveys of AAAAI members on immunotherapy fatalities spanning time period between
1945-2001
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 3 4
1.
2.
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):288-94.
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
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 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
AAAAI/ACAAI Surveillance Study of SCIT Safety:
Time of Onset and Grade
No. of Systemic Reactions
Per injection SR rate & number (%) practices reporting1
Grade 1 mild SR:
74%
1 per 1,287 (.07% injection visits)
6,293
613 (76%) practices
Grade 2 moderate SR:
1 per 4,166 (.02% injection visits)
23%
1,944
436 (54%) practices
3%
Grade 3 severe SR:
265
1 per 30,566 (.003%)
Grade 1 Grade 2 Grade 3
144 (18%) practices
Mild
Moderate Severe
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.
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 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
1. Confino-Cohen et al, Ann Allergy Asthma Immunol 2010;104:73-8.
2. Scranton et al, J Allergy Clin Immunol 2009;123:493-8.
17
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.
18
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 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.
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):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 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.
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
Copenhaver 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: 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):247-52.
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
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.
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
Severity of First Systemic Allergic Reaction
Number of Patients
Patients who experienced SR: omalizumab 13.5%, placebo 26.2%
P= 0.017
30
24
25
20
15
10
7
6
5
6
2
2
0
2
0
Grade 1 (Skin)
Grade 2 (GI)
Omalizumab
N=17
Grade 3
(Resp)
Placebo
N=32
Massanari et al, J Allergy Clin Immunol. 2010;125(2):383-9
Grade 4 (CV)
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 βblockers….
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 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.
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.
1.
2.
3.
4.
White KM, England RW. Ann Allergy Asthma Immunol 2008; 101:426-30.
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;124:1047-54.
34
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.
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
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)
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 )
Author,
year
N
pts
Age
range
FollowUp
Di Rienzo, 1999
Lombardi, 2001
Pajno, 2003
Fiocchi, 2005
Drachenberg,
2004
Agostinis, 2005
Di Rienzo, 2005
Rodriguez, 2008
Agostinis, 2008
Lombardi, 2008
268
198
354
65
159
2-15
18-65
5-15
3-7
6-60
3 years
3 years
3-4 years
1 year
< 1 year
Total AE
% of
Patients
3 %*
5.5 %
6%
15%
6.3%
36
128
43
433
159
3-5
3-5
8-20
3-18
16-59
2 years
2 years
1 year
1 year
1 year
5%
5. 6%
11.6%*
41%
63%
Total
Local AE
AE/1000 % of patients
Doses
0.083*
7%
0.5
1.5%
0.15
Not stated
Not stated
6%
Not stated
5%
0.07
0.2
0.3
4.4
6.5
* including systemic side effects only
Passalacqua et al, Grading side effects of sublingual immunotherapy speaking the same
language. 2011 in preparation
Not stated
1.5%
46%
32%
41%
Author, year Sex (age) Allergen
Phase
(producer)
De
Groot, M (13) Grass (Grazax, First dose
2009
ALK-Abellò)
De
Groot, F (27)
Grass (Grazax, First dose
2009
ALK-Abellò)
Blazowski,
2008
F (16)
Eifan, 2008
F (11)
Dunski, 2006 F (31)
Antico, 2006 F (36)
Onset
Description
15 min
Generalized urticaria, NO
swelling of tongue
Abdominal
cramps, YES
asthma,
generalized
itching, hypotension
Hypotension-collapse, YES
flushing, urticaria
5 min
HDM (Staloral, Maintenance 10 min
overdose (60
Stallergenes)
drops)
dust mite + grass Maintenance. 3 min
pollen
mix
(Stallergenes)
Alternaria, cat, 2nd day of 5 min
dog
updosing
grass, ragweed,
(Greer)
End of
Latex
10 min
rush buildup
Epinephrine
Abdominal pain, chest Not
pain, fever, nausea
specified
Angioedema, dizziness, NO
dyspnea, generalized
itching
Asthma,
urticaria
generalized 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 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
42
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
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
43
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: 181-184
Comparison of 2 vs. 4 Month Pre & Co-seasonal Grasspollen 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
Randomized patients = 633
Placebo = 219
300IR (2M) = 207
300IR (4M) = 207
205 (94%)
year 1
(2007)
188 (91%)
year 1
(2007)
188 (91%)
172 (79%)
year 2
(2008)
155 (75%)
year 2
(2008)
160 (77%)
165 (75%)
year 3
(2009)
147 (71%)
year 3
(2009)
149 (72%)
155 (71%)
year 4
(2010)
137 (66%)
year 4
(2010)
143 (69%)
•
Didier et al, J Allergy Clin Immunol. 2011;128(3):559-66
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
MOUTH/
EAR
UPPER
GASTRO
INTESTINAL
LOWER
GASTRO
INTESTINAL
LOCAL SIDE EFFECT
MeDRA PREFERRED
TERM
MeDRA
CODE
MeDRA
Low level term (LLT)
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
Nausea
Nausea
10028813
Nausea
Stomach-ache
Abdominal pain upper
10000087
Stomach ache
Vomiting
Vomiting
10047700
Vomiting
Abdominal pain
Abdominal pain
10000081
Abdominal pain
Diarrhea
Diarrhoea
10012735
Diarrhea
Passalacqua et al, Grading side effects of sublingual immunotherapy speaking the same language. 2011 in preparation
WAO Grading System for SLIT Local Reactions
Symptom/sign
Abdominal pain,
Diarrhea
Ear itching
Pruritus/swelling
of mouth,
tongue or lip
Nausea
Throat irritation
Uvular oedema
Vomiting
Grade 1 – Mild
Grade 2 –
Moderate
● Not
● Troublesome 
troublesome
OR
AND
● Requires

● No symptomatic symptomatic
treatment required treatment
AND
AND
● No
●No
discontinuation
discontinuation of
of SLIT because
SLIT because of
of local side
local side effects
effects
Grade 3 Severe
Grade 2
AND
SLIT
discontinued
because of
local side
effects
Unknown
severity
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
Passalacqua et al, Grading side effects of sublingual immunotherapy speaking the same language. 2011
in preparation
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.
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
WAO SLIT Position Paper
SLIT appears to be better tolerated than SCIT
Paris 2009
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
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.
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
Formulations And Routes:
Looking Toward The Future
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 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 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
Reasons 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 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;124:997-1002.
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
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 rush
1.3% 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 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!!!!