Symposium: Immunotherapy in Latin America - WISC 2014- Rio de Janeiro Symposium 5: Latin American Society of Allergy and Immunology (SLAAI) Symposium: Immunotherapy in Latin America Sala 1 & 2 (Sul America)

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
Confound
annulated*
Dose- response gradient
TOTAL (+)
Limitations in 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-ALOH grass (and tree) pre-season for 3 years.
12yrs post 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 symptoms
No
No
No
0
No
Asthma only measured by subjective symptoms
No
No
-2
0, Very low
New sen- sitizations
No
P<0.05, even though groups are small
No
+1
No
No
No
No
-1
2, low
Keskin 2006{Keskin 2006}
SAR (mild asthma)
27 SCIT, 26 control; 6-18y
Allergoid-ALOH grass,
20mcg Phl 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
20mcg Phl p 5 or 12 Bet v 1(eq)/6w Duration: 3 years
7 yrs post immunotherapy
RCT (4) AR symptoms/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 {Roberts 2006}
Asthma and AR
18 SCIT, 17 Placebo; 3-16y
ALOH grass SCIT
20mcg Phl p 5 (eq)/6w Duration: 18mo
DBPC
(4)
No
No
No
0
No
No
No
No
No
0
High
Kuna 2009 {kuna 2009} AR/ Asthma mild-moderate DBPC (4)
Rhinoconj.
No
No
Time/dose- +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.use 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
oRandomized, controlled Jacobsen 2007
•SCIT 12 years
oOpen controlled Eng 2008
•SLIT: 2 years
oDBPC Durham 2012, Didier 2013
•SLIT: 6 years (metacholine), 7-8y symptoms:
oRetrospective: 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
% of countries*
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
Weighted average daily pollen counts
(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
Combined mean difference
(placebo - Grass SLIT*)

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
Δ Symptom Score Unit
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
*
Δ Log10 Dose (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
Der p 1 and 2 Concentration
(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