Immunotherapy in Children: Sublingual or Subcutaneous? Dra. Desirée Larenas

1. IMMUNOTHERAPY IN CHILDREN:
SUBLINGUAL OR SUBCUTANEOUS?

2. DISCLOSURE
 Dr Larenas has received speaker’s fees from Merck-
Sharp-Dôhme, Astra-Zeneca, Pfizer, Novartis, MEDA;
Travel grants from Sanofi, Novartis, UCB, MSD,
Astrazeneca, Pfizer, Senosiain and is member of the
advisory board of Pfizer, Novartis, MEDA.

3. EXAMPLE CASE
 Mexico: 4yo male with allergic rhinitis symptoms all year long,
exacerbating in spring with wheezing and when he goes to
grandma’s home where there is a cat.
From 0-2 years he lived in a humid basement appartment.
His mother does not want to give him so much medication any
more.
 SPT positive for D pteronyssinus, cat, Alternaria and Phleum and
Poa pratense.
 Would you give Immunotherapy?
 With D pteronyssinus?
With cat?
With Alternaria ?
With Phleum pratense?
 SCIT or SLIT?
 If SLIT: drops or tablets, mono or multi?

4. SUBLINGUAL OR SUBCUTANEOUS?
 Safety
 Efficacy
 In trials:
Efficacy demonstrated per allergen and per allergic
disease
 In real life:
 Correct diagnosis
 Long-term efficacy
 Mono-multi allergic patients
 Adherence ~ Patient’s preference
 Not all SLIT, is SLIT

5. SAFETY OF IMMUNOTHERAPY AND
(RELATIVE) CONTRAINDICATIONS

6. SAFETY SLIT
 No fatalities
 Several anaphylactic reactions (1 o 8 in total: 16yo)
 Eosinophilic esophagitis (1 report grass pollen SLIT)
 Hsieh, F. H. (2014). "Oral food immunotherapy and iatrogenic eosinophilic
esophagitis: an acceptable level of risk?" Ann Allergy Asthma Immunol
113(6): 581-582.
 Metanalysis: 2.7% in oral food immunotherapy: milk, egg, peanut.
Lucendo, A. J., et al. (2014). "Relation between eosinophilic esophagitis and
oral immunotherapy for food allergy: a systematic review with meta-
analysis." Ann Allergy Asthma Immunol 113(6): 624-629
 44yo: Miehlke, S., et al. (2013). "Induction of eosinophilic esophagitis by
sublingual pollen immunotherapy." Case Rep Gastroenterol 7(3): 363-368.

7. SAFETY SCIT
(NEAR) FATALITIES
 1920-40ies: deaths with intradermal skin testing in 3 pre-school
children
 Lockey 2001: several cases (5 or more - no exact count, age-ranges,
most asthma)
 Amin 2006: 6 (9%) of non-fatal reactions in children 5-12y, 5 had
asthma
 US surveillance study (Bernstein et al.): NO CHILD1
 1 fatality 2008-2012
1/23.3 million injection visits
 Very severe, WAO grade 4, SRs (near-fatal reactions)
1/1,000,000 injections
 No fatalities officially reported in rest of the world
Epstein, T. G., et al. (2014). "AAAAI/ACAAI surveillance study of subcutaneous
immunotherapy, years 2008-2012: an update on fatal and nonfatal systemic
allergic reactions." J Allergy Clin Immunol Pract 2(2): 161-167

8. SURVEY AAAAI MEMBERSHIP
2012-13
 21% response rate (1085 AAAAI members)
 Expresses their experience with immunotherapy patients
 CAVE: Recall bias
In allergic patients with certain medical conditions:
1. Do you think immunotherapy is contra-indicated?
2. From what age onward would you give SCIT?
3. What has been your experience in giving AIT to these
patients?

10. FROM WHAT AGE ONWARD
WOULD YOU GIVE SCIT?
 2 years onward: 6% (58/996)
 3 years onward: 15% (147/996)
 4 years onward: 30% (286/996)
Larenas Linnemann D, Hauswirth D, Calabria C, Sher L, Rank M. AAAAI Survey On Allergen Immunotherapy
(AIT) In Patients With Specific Medical Conditions. J Allergy Clin Immunol 131(2 Phase I), AB229 (2013).

11. 5423
4129
3518
3075
2524
2442
1975
1329
720
420
184 179 174 142
0
1000
2000
3000
4000
5000
6000
Total number of patients* with the medical condition
that has been treated with SCIT by physician
respondents
Children under 5y:
2,013
Larenas Linnemann D, Hauswirth D, Calabria C, Sher L, Rank M. AAAAI Survey On Allergen Immuno-
therapy (AIT) In Patients With Specific Medical Conditions. J Allergy Clin Immunol 131(2 Phase I), AB229 (2013).

12. 172
30
81
445
328
191
402
468
201
292 256
543
482
83 93
290
5
11
73
67
36
80
143
19
86
45
92
43
10 10
66
14
4
10
7
4
8
9
2
3
2
4
1
0 0
0
100
200
300
400
500
600
700 No problems
Minor problems
Mayor problems
Experience of those respondents giving SCIT to patients with an
underlying medical condition: outcomes (Nr. of physicians (%))
1.9%
1.7%
12.5%
5.4%
4.2%
1.7%
1.6%
1.5%
Less than 1%
Children under
5 years: 0.8%
Larenas Linnemann D, Hauswirth D, Calabria C, Sher L, Rank M. AAAAI Survey On Allergen Immuno-
therapy (AIT) In Patients With Specific Medical Conditions. J Allergy Clin Immunol 131(2 Phase I), AB229 (2013).

13. EFFICACY: THE TRIALS

14.  All asthmatic children that came to the department
 No informed consent: did not know they were in a study
 All received SCIT till they were 15 years of age
 Randomly assigned to 4 dosing groups

15. Johnstone DE, Crump L. Value of hyposensitization therapy for perennial
bronchial asthma in children. Pediatrics. 1961 Jan;27:39-44.
N=
173
42
49
39
43

16. Johnstone DE, Crump L. Value of hyposensitization therapy for perennial
bronchial asthma in children. Pediatrics. 1961 Jan;27:39-44.

17. Johnstone DE, Crump L. Value of hyposensitization therapy for perennial
bronchial asthma in children. Pediatrics. 1961 Jan;27:39-44.

18. From which age onward?

19. From which age onward?

20. GRADE approach of evaluating
quality of evidence
Study design Add or subtract
points
depending
on certain
characteristics
Augment quality if... Reduce quality if... Calculate final
quality of
evidence
Quality of
evidence
Randomized (4) Large effect***
1. Large
2. Very large
Dose-response
1. Evidence of a
gradient
All plausible
confounding
1. Would reduce a
demonstrated
effect, or
2. Would suggest a
spurious effect
when results show
no effect
Study limitations*
1. Serious
2. Very serious
Inconsistency
1. Serious
2. Very serious
Indirectness
1. Serious
2. Very serious
Imprecision**
1. Serious
2. Very serious
Publication bias
1. Likely
2. Very likely
High (4)

Moderate (3)

Observational (2) Low (2)

Very low (1)

Brozek JL, Akl EA, Alonso-Coello P, Lang D, Jaeschke R, Williams JW, et al.
Grading quality of evidence and strength of recommendations in clinical practice guidelines. Part 1 of 3. An
overview of the GRADE approach and grading quality of evidence about interventions. Allergy. 2009 May;64(5):669-77]

21. Larenas-Linnemann, D. E., et al. (2011). Ann Allergy Asthma Immunol 107(5): 407-416

22. Author, year
Some study details
Design
(Starting
score)
Large
effect
Confoun
d
annulate
d*
Dose-
response
gradient TOTAL (+)
Limitationsin
design /
execution
Inconsis-
tency of
results
Indirectness
of evidence
Impreci-
sion of
results
Publ
bias
TOTAL
(--)
Quality
of
evidence
SEASONAL ALERGIC RHINITIS/ASTHMA STUDIES
Eng 2006 {eng 2006}
SAR (mild asthma)
12 SCIT, 10 control; 5-16y
Allergoid-ALOHgrass (and
tree)
pre-seasonfor 3 years.
12yrspost immunotherapy
OCT (2)
AR
Sympt+
Med
reduction
No P<0.03,
even
though
groups
are small
No +1
No sample size
calculations
No No No No -1 2, Low
Seasonal
Asthma
symptom
s
No No No 0 No Asthma only
measured by
subjective
symptoms
No No -2 0, Very
low
New sen-
sitization
s
No P<0.05,
even
though
groups
are small
No +1 No No No No -1 2, low
Keskin 2006{Keskin2006}
SAR (mild asthma)
27 SCIT, 26 control; 6-18y
Allergoid-ALOHgrass,
20mcgPhl p 5(eq)/6w
Duration:27 mo
OCT (2) No No No 0 Second season
18 extra
controls
added, no
calculation
sample size
No No No No -1 1, very
low
Jacobsen 2007{Jacobsen
2007}
SAR (mild asthma)
79 SCIT, 68 control; 6-14y
AL-OH grass or birch SCIT
20mcgPhl p 5 or 12 Bet v
1(eq)/6w
Duration:3 years
7 yrs post immunotherapy
RCT (4)
AR
symptom
s/med
No No No 0 Drop-out in
controls 33%
(at 7yrs post-
IT: deduction
0.5)
No RC
symptoms
only
evaluated
with VAS
No No -1.5 2-3,
moderate
New
asthma
OR at
7yrs post-
IT: 4.6
(CI95%
1.5-13.7)
No No +1 No difference
Bronchial
provoca-tion
test
No No No -1.5 3-4,
moderate
-high
Roberts 2006 {Roberts2006}
Asthma and AR
18 SCIT, 17 Placebo; 3-16y
ALOH grass SCIT
20mcgPhl p 5 (eq)/6w
Duration:18mo
DBPC
(4)
No No No 0 No No No No No 0 High
Kuna 2009 {kuna 2009}
AR/ Asthmamild-moderate
DBPC (4)
Rhinoconj
No No Time/dos
e-
+1 No No No No No 0 High

23. Larenas-Linnemann, D. E., et al. (2011). Ann Allergy Asthma Immunol 107(5): 407-416

24. Larenas-Linnemann, D. E., et al. (2011). Ann Allergy Asthma Immunol 107(5): 407-416

25. SLIT INDICATIONS: AGE
Author, year
Some study details
Design
(Starting
score) Large effect
Con-
found
Annula-
ted*
Dose-
response
gradient TOTAL (+)
Limitations
in design /
execution
Incon-
sistent
results
Indirectness of
evidence
Imprecision of
results
Publ
bias
TOTAL
(--)
Quality of
evidence
Wahn 2009 (1)
SAR (21% mild asthma)
131 SLIT, 135 Plac
4-17y; pre-coseason
25mcg grp 5 grass tabl/d
DBPC
(4)
X X X 0 X X X X X 0 Rhinitis
reduction:
High
Bufe 2009 (2)
SAR (42% mild asthma)
114 SLIT, 120 Placebo;
5-16yrs, Pre-coseason
15mcg Phl p 5 tablet/day
DBPC
(4)
Rhinitis
X X X 0 X X X X X 0 Rhinitis
reduction:
High
DBPC
(4)
Asthma
X X X 0 X X Only symptom +
medication
Very small
numbers
(9 vs 3 days)
X -2 Asthma
reduction:
Low
Rdriguez-Santos ‘08 (3)
Asthma and/or rinitis
HDM 69, placebo 69;
2-5 years; for 2 years
Intermediate dose daily
RCT
(4)
RR
emergency
visit 0.39;
Corticoster.u
se 0.37
X X +1 No conceal-
ment of
allocation, no
blinding
X x No symptoms
analyzed
No report
other
med
-3 Asthma/
rhinitis
reduction:
Low
Stelmach 2009 (4)
Asthma mild-moderate
persistent
20 SLIT, 15 Placebo
6-17y; pre-coseason x 2y
10mcg grp 5 grass drops
daily
DBPC
(4)
+1 X X +1 40% drop-out
placebo
group.
Sympt/med
adjusted for
pollen count
X X No pollen
count reported
X -3 Asthma
reduction:
Low
Agostinis 2008 (5)
Safety, mono- vs multiple
pollen SLIT
179 single pollen SLIT,
254 multiple
3-18 yrs; during 6-24 mo
Various manufacturers,
dosing varied
Post-
market
(2)
X X X 0 No blinding of
outcome
X X X X -1 Safety data:
Very low
1. Wahn U, et al. J Allergy Clin Immunol. 2009 Jan;123(1):160-6
2. Bufe A, et al. J Allergy Clin Immunol. 2009 Jan;123(1):167-73
3. Rodriguez-Santos O. Revista Alergia México. 2008;55(2):71-5.
4. Stelmach I, et al. Clin Exp Allergy. 2009 Mar;39(3):401-8.
5. Agostinis F, et al. Allergy. 2008 Dec;63(12):1637-9.
Larenas-Linnemann D. Curr Opin Allergy Clin Immunol. 2009 Dec;9(6):558-67.

26. From which age onward?

27. From which age onward?

28. From which age onward?
SLIT:
Blaiss 2012 (US) : 5 years
Larenas-Linnemann 2009: 4 year high Q (2 years: very low Q)
Larenas-Linnemann 2013: 4 years high Q
SCIT:
Larenas-Linnemann 2012: 5 years (Roberts: 3 years high Q)

29. EFFICACY: REAL LIFE

30. Real life: Long term efficacy
• SCIT: 7 years
o Randomized, controlled
Jacobsen 2007
• SCIT 12 years
o Open controlled
Eng 2008
• SLIT: 2 years
o DBPC
Durham 2012, Didier 2013
• SLIT: 6 years (metacholine), 7-8y symptoms:
o Retrospective: Depends on duration of SLIT: 7-8 years only after 4 years SLIT
Marogna Int Arch Allergy Immunol 2007

31. Real life: SLIT: Mono-Multi issues
1. Does mono-allergen SLIT work in multi-sensitized patients?
2. Is mono-allergen SLIT safe in multi-sensitized patients? (pollen)
3. Does duo-allergen SLIT work in duo-allergic patients?
4. Does multi-allergen SLIT work in allergic patients?

32. 0
50
100
No mixing Only 2 3-5
allergens
6-10
allergens
11
56
67
22
%ofcountries*
Number of allergens mixed in one vial
Number of allergens mixed in one vial:
Latin American countries
* In some countries several answers were given by respondents, we scored them all
Baena-Cagnani, C. E., Larenas-Linnemann D, et al. (2013). "Allergy training and immunotherapy
in Latin America: results of a regional overview." Ann Allergy Asthma Immunol 111(5): 415-419 e411.

33. Efficacy Grazax® in Mono vs. sensitized:
Difference in sympt-medication scores (mean)
0
0.5
1
1.5
2
2.5
Sólo césped Césped +
1alergeno
Césped +
2+alergenos
1.62
n=161
1.70
n=170
2.15
n=237
* Percentage reduction rounded to 1 d.p
*75,000 SQ-T/2,800 BAU Phleum pratense, ALK-Abelló
Days since start of the season
Weightedaveragedailypollencounts
(grains/m3)
0
10
20
30
40
50
60
70
80
90
100
110
120
130
140
150
0 20 40 60 80 100
2005 pollen season
Mean combined difference
grass SLIT vs. placebo
Courtesy: M.Calderón
Combinedmeandifference
(placebo-GrassSLIT*)

34. Pollen sensitization type
One grass Grass + 1 allergen
Grass + 2 or more
allergens
Treatment Grass SLIT Grass SLIT Grass SLIT P-value**
TEAE: Sí
No
74
17
79
11
112
23
0.7159
Relación c/ Tx: Sí
No
63
28
71
19
103
32
0.2720
Prurito oral: Sí
No
41
50
43
47
61
74
0.3191
Nasofaringitis
No
14
77
16
74
17
118
0.9985
Edema boca: Sí
No
13
78
17
73
28
107
0.5030
Influenza: Sí
No
7
84
3
87
13
122
0.4260
Prurito oído: Sí
No
16
75
12
78
10
125
0.2303
Irritación garganta:
Sí
No
9
82
9
81
12
123
0.3413
Cefalea: Sí
No
4
87
1
89
4
131
0.4304
Subjects with SLIT presenting treatment related adverse events:
no differences between the mono- vs polysensitized
* Safety population; N=634; ** p value obtained using CMH test (general association) controlled for pollen sensitization type Cortesía: M.Calderón

35. Dual SLIT in dual-allergics
SLIT Birch only / grass only / Birch + grass
Marogna M, et al. Ann Allergy Asthma Immunol. 2007 Mar;98(3):274-80.

36. Dual grass-HDM SLIT drops reduces
symptoms, medication and improves SPT and nasal challenge
Swamy, R. S., et al. (2012). "Epigenetic modifications and improved regulatory T-cell function in
subjects undergoing dual sublingual immunotherapy." J Allergy Clin Immunol 130(1): 215-224 e217

37. TM MAT Placebo
∆SymptomScoreUnit
Symptom Score
P=.96
-4.50
-4.00
-3.50
-3.00
-2.50
-2.00
-1.50
-1.00
-0.50
0
Sympto
ms Medication
Nasal
provocation
Titrated
SPT
Specific
IgE
Specific
IgG4
Tim NS NS 0.03 0.001 0.008 0.005
Tim+9 NS NS NS 0.04 0.02 NS
Placebo NS NS NS NS NS NS
Multi-mix SLIT: The Amar-Nelson Study
-0.60
-0.40
-0.20
0
0.20
0.40
0.60
0.80
1.00
1.20
TM MAT Placebo
*∆Log10Dose(BAU/mL)
Tirated Nasal Challenge
Tim T+9 Placebo Mono T+9 Placebo

38. SLIT : Mono-Multi issues
1. Does mono-allergen SLIT work in multi-sensitized patients?
2. Is mono-allergen SLIT safe in multi-sensitized patients?
(pollen)
3. Does duo-allergen SLIT work in duo-allergic patients?
4. Does multi-allergen SLIT work in allergic patients?
Yes
Yes
Less
Yes

39. Real life: Adherence
• Dutch study: Adherence in real life (pharmacy data):
18% finishes 3 years. Median durations for SCIT and SLIT users
were 1.7 and 0.6 years, respectively (P < .001).
Kiel MA, et al. Allergy Clin Immunol 132(2): 353-360 e352.
• Miami: low adherence for SCIT
Hankin et al. J Allergy Clin Immunol 127(1): 46-48, 48 e41-43.
• Anolik in US
Anolik, R., et al. (2013). "Persistence with Specific Immunotherapy
(SCIT & SLIT) Among AR Patients in A US Allergy Practice." J Allergy
Clin Immunol 131(2, suppl): AB186.

40. SLIT vestibular
• Células cebadas: localizadas en glándulas
• Langerhans cells: densidad más alta en región
vestibular, densidad más baja en región sublingual
Allam et al. Allergy. 2008 Jun;63(6):720-7.

41. SLIT IS NOT SLIT

42. Relative monthly SLIT doses
Monthly doses of SLIT maintenance therapy given with the products of
four prominent European manufacturers,
relative to the US recommended SCIT monthly maintenance dose*
Manufacturers D pteronyssinus Timothy Cat Short
ragweed
Eur1 1 2 2 5
Eur2 1 21 1 42
Eur3 3 57 13 68
Eur4 16 94 31 237
* Monthly probably effective doses recommended in US for SCIT are given a relative value of 1.
For house dust mite 1 = 1000AU, timothy grass pollen 1 = 2000BAU, cat 1 = 3.8 Fel d 1 Units and
Short Ragweed pollen 1 = 9 Amb a 1 Units.(2)
A wide range of different quantities of
allergen given in nowadays
SLIT in Europe
Larenas-Linnemann D, Esch R, Plunkett G, Brown S, Constable D, et al.
Ann Allergy Asthma Immunol 107(5): 448-458 e443.

43. Extracts that have shown efficacy in trials
Relative monthly doses of SLIT maintenance therapy of four
prominent European manufacturers*
Manu-
facturers
D pteronyssinus Timothy Cat Short
ragweed
Eur1 1 2 2 5
Eur2 1 21 1 42
Eur3 3 57 13 68
Eur4 16 94 31 237
* Monthly probably effective doses recommended in US for SCIT are given a relative value of 1.
For house dust mite 1 = 1000AU, timothy grass pollen 1 = 2000BAU, cat 1 = 3.8 Fel d 1 Units
and Short Ragweed pollen 1 = 9 Amb a 1 Units.
Larenas-Linnemann D, Esch R, Plunkett G, et al.
Ann Allergy Asthma Immunol 107(5): 448-458 e443

44. Diferente composición extractos de
ácaros: EEUU y Europea
Content of major allergens Der p 1 and Der p 2
0
10
20
30
40
50
60
70
80
90
Eur1 Eur2 Eur3 Eur4 US1 US2 US3 FDA
Lab1 Der p 1 Lab2 Der p 1 Lab1 Der p 2 Lab2 Der p 2
Derp1and2Concentration
(µg/mL)
Larenas-Linnemann D, Esch R, Plunkett G, Brown S, Constable D, et al.
Ann Allergy Asthma Immunol 107(5): 448-458 e443.
SLIT maintenance solutions SCIT concentrates

45. Relative potency (BAU) of grass Tablets
4.200BAU 7.300 BAU
• Grazax® 15mcg Phl p 5 (2.800 BAU)
• 10.000 BAU Phleum pratense 1.56cm2 wheal surface.
• Tablets wheal surfaces correspond with 4.200 – 7.300 BAU
Larenas Linnemann D, Singh J, Esch R, IMSIE Cologne et al. WISC 2014 Poster 1044

46. EXAMPLE CASE
 Mexico: 5yo male with allergic rhinitis symptoms all year long,
exacerbating in spring with wheezing and when he goes to
grandma’s home where there is a cat.
From 0-2 years he lived in the basement.
His mother does not want to give him so much medication any
more.
 SPT positive for D pteronyssinus, cat, Alternaria and Phleum and
Poa pratense.
 Would you give Immunotherapy?
 With D pteronyssinus?
With cat?
With Alternaria ?
With Phleum pratense?
 SCIT or SLIT? Can he come to your clinic? If NO: SLIT
 If SLIT: drops or tablets, mono or multi?

47. WHAT IS THE PREFERABLE ROUTE?
DEPENDS ON:
 Correct diagnosis: which allergens?
 Allergic!! Symptoms on probable exposure
 Availability of quality products
 SCIT standardized, where possible
 SLIT: high local concentration
 Multi-allergic: SCIT might be preferable
 Logistics and Preference of the patient:
ADHERENCE
 Age: SCIT And SLIT: 4years, 3y (?)

48. COOPERATION
Latin-America
Europe
Far-East
US