Immunotherapy in children SCIT or SLIT. Dra. Desirée Larenas WISC Dec2014 Rio de Janeiro Brasil

IMMUNOTHERAPY IN CHILDREN:

SUBLINGUAL OR SUBCUTANEOUS?

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.

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?

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

SAFETY OF IMMUNOTHERAPY AND

(RELATIVE) CONTRAINDICATIONS

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.

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

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?

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).

5423

4129

3518

3075

2524 2442

1975

1329

720 420

184 179 174 142 0

1000

2000

3000

4000

5000

6000Total 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).

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).

EFFICACY: THE TRIALS

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

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



From which age onward?


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]

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

Author, year

Some study details

Design

(Starting

score)

Large

effect

Confoun

d

annulate

d*

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

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{Keskin 2006}

SAR (mild asthma)


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)


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

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 {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

persistent

30 SCIT, 20 Placebo; 5-18y

ALOH alternaria

8mcg Alt a 1/ 4-6w for 36mo

DBPC (4)

Rhinoconj

.

No No Time/dos

e-

gradient

first-2nd-

third year

+1 No No No No No 0 High

Asthma No No +1 No No No No No 0 High

Tabar 2008 {Tabar 2008}

Asthma mild-moderate

persistent (AR)

14 SCIT, 14 Placebo; mean

12y

Alternaria 0.1mcg Alt a 1/ 4w

for 12mo

DBPC (4)

Rhinoconj

No No No 0

Sample size

not reached.

Medication

score

improved in

placebo

No No No -2 Low

Asthma No No No 0 No No No -2 Low

Zapatero 2010 {Zapatero

2010}


persistent (AR)

99 SCIT, 4-16y

AlOH alternaria

0.2mcg Alt a 1/ 4w for 12mo

Open (2)

Rhinoconj

No No No 0 No No No No No 0 Low

Asthma ICS

reduction

p<0.0007,

ACT

p<00001

No No +1 No objective

measures of

asthma control

No No No No -1 Low



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)


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.




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)

EFFICACY: REAL LIFE

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

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?

0

50

100

No mixing Only 2 3-5

allergens

6-10

allergens

11

56 67

22

% o

f co

un

trie

s*

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.

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

Wei

gh

ted

av

erag

e d

aily

po

llen

co

un

ts

(gra

ins/

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

Co

mb

ined

mea

n d

iffe

ren

ce

(pla

ceb

o -

Gra

ss S

LIT

*)

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

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.

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

TM MAT Placebo

∆ S

ym

pto

m S

core

Un

it

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

* ∆

Lo

g10

Do

se (

BA

U/m

L)

∆ S

ym

pto

m S

core

Un

it

Tirated Nasal Challenge

Tim T+9 Placebo Mono T+9 Placebo

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

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.

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.

SLIT IS NOT SLIT

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.

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.

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

an

d 2

Co

nce

ntr

atio

n

(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

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

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?

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 (?)

COOPERATION

Latin-America

Europe

Far-East

US

Date post:	10-Jul-2015
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Immunotherapy in children SCIT or SLIT. Dra. Desirée Larenas WISC Dec2014 Rio de Janeiro Brasil

Health & Medicine