Preventive effect of AIT over the atopic march

Preventive effect of AIT over the atopic march Susanne Halken, Professor, Pediatric Allergist Hans Christian Andersen Children s Hospital Odense University Hospital, DK

Type Disclosure In relation to this presentation, I declare the following, real or perceived conflicts of interest: Employment full time / part time Spouse / Family member employment / engagement Research Grant (P.I., collaborator or consultant; pending and received grants) Other research support Speakers Bureau / Honoraria Ownership interest (stock, stock-options, patent or intellectual property Consultant / advisory board Company None None None None Honoraria for lectures at scientific meetings for different companies None ALK-Abelló: Member of the Steering group for the GAP study A conflict of interest is any situation in which a speaker or immediate family members have interests, and those may cause a conflict with the current presentation. Conflicts of interest do not preclude the delivery of the talk, but should be explicitly declared. These may include financial interests (eg. owning stocks of a related company, having received honoraria, consultancy fees), research interests (research support by grants or otherwise), organisational interests and gifts.

Prevalence (%) Allergic diseases natural course atopic march allergic rhinitis asthma food allergy atopic eczema 0 ½ 1 3 7 15 Age (years)

Allergic diseases Very frequent Major impact on quality of life Huge socio-economic impact High risk of comorbidity AR > 3-fold risk of developing asthma AIT for prevention?? Burgess JA JACI 2007

AIT disease modifying effect? Sustained, longterm effect beyond treatment Preventive effect indicated Development of new allergic disease e.g. asthma In healthy individuals In patients with already developed disease Development of new sensitivities

EAACI AIT Guidelines CPGs are statements that include recommendations intended to optimize patient care that are informed by a systematic review of evidence and contain an assessment of the benefit and harms

Included studies Identified through database searching: n = 11840 15 RCTs García, Grembiale, Szépfalusi, Zolkipli Crimi, Limb, Möller, Novembre, Pifferi Dominicus, Jacobsen, Marogna (2004 & 2008), Song, Yamanaka 15 CBAs Asero, Des Roches, Di Rienzo, Eng, Gulen, Harmanci, Inal, Marogna (2010), Ohashi (2 studies reported in 1 paper), Pajno, Purello-D Ambrosio, Reha, Schmitt, Tella Quality appraisal: Low, moderate & high risk of bias The GAP trial (Valovirta 2017) & Real life study (Zielen 2017) Kristiansen M. PAI 2017

Methods Data were descriptively summarized and where possible and appropriate, quantitatively synthesised using randomeffects meta-analyses to assess: the short-term (i.e. within 2 years of end of AIT), & longer-term (i.e. 2 years post-ait) benefits of AIT

Results 1 First allergic disease in healthy individuals No conclusive evidence that AIT reduced the risk of developing a new first allergic disease over the shortterm or the longer-term effects Yamanaka 2015, Zokipili 2015 New allergic disease in individuals with AD No conclusive evidence Only one small pilot study. 50 infants with AD, +FH, + sige; SLIT, drops, mixed aeroallergens. Holt PG. JACI 2013 Kristiansen M. PAI 2017

Results 2 Short-term (< 2 yrs) prevention of asthma in those with AR Random-effects meta-analysis of effectiveness of AIT Author/year RR (95% CI) Crimi, 2004 Grembiale, 2000 Marogna, 2008 Möller, 1986 Möller, 2002 Novembre, 2004 Overall (I-squared = 0.0%, p = 0.429) 0.29 (0.07, 1.16) 0.20 (0.01, 3.94) 0.28 (0.17, 0.48) 0.10 (0.01, 1.71) 0.54 (0.34, 0.87) 0.49 (0.23, 1.02) 0.40 (0.30, 0.54).0062 1 161

Results 2 Short-term (< 2 yrs) prevention of asthma in those with AR Random-effects meta-analysis of effectiveness of AIT Author/year RR (95% CI) Crimi, 2004 Grembiale, 2000 SCIT Parietaria 3yrs SCIT HDM 2 yrs 0.29 (0.07, 1.16) 0.20 (0.01, 3.94) Marogna, 2008 SLIT micl 0.28 (0.17, 0.48) Möller, 1986 Möller, 2002 Novembre, 2004 Overall (I-squared = 0.0%, p = 0.429) Oral birch 10 mos 0.10 (0.01, 1.71) 0.54 (0.34, 0.87) SCIT birch/grass 3 yrs SLIT grass 3 yrs 0.49 (0.23, 1.02) 0.40 (0.30, 0.54).0062 1 161

Results 3 Short-term prevention of asthma in those with AR Reduction in the development of asthma (pooled RR=0.32; 95% CI 0.22 to 0.48), with this finding being robust to a prespecified sensitivity analysis Predefined subgroup analyses showed that AIT was beneficial in: Children/adolelescents aged < 18 yrs Greater impact by 3 yrs of AIT vs < 3 yrs of AIT SLIT and SCIT Pollen AIT but lack of evidence for HDM AIT

Results 4 Long-term ( 2 yrs) prevention of asthma in those with AR Random-effects meta-analysis of effectiveness of AIT Author/year Author, year RR (95% CI) RR (95% CI) Jacobsen, Jacobsen, 2007 Song, 2015 Song,2015 Valovirta, Valovirta, 2017 Overall (I-squared = 63.6%, p 0.084) Overall (I-squared = 63.6%, p = 0.064) Jacobsen 2007: 0.55 (0.33, SCIT 0.93) birch/grass 3 yrs 0.55 (0.33, 0.93) 0.05 (0.00, 0.88) Song 2015: SCIT HDM 3 yrs 0.05 (0.00, 0.88) 0.91 (0.58, 1.41) Valovirta 2016: SLIT grass 3 yrs 0.62 (0.31, 1.23) 0.91 (0.58,1.41) 0.62 (0.31,1.23).00314 1 318 no overall evidence 0.0314 of a long-term 1 1 reduction 318 in the risk of developing asthma: RR=0.62; (95% CI 0.31,1.23)

GAP trial (GRAZAX Asthma Prevention) No effect in terms of time to first diagnosis of asthma with primary outcome: reversible impairment of lung function Significantly reduced proportion of children experiencing asthma symptoms or using asthma medication (OR 0.66 [0.45;0.97], p 0.036). This effect was sustained 2 years post treatment Valovirta E, JACI 2017

Proportion of subjects Asthma symptoms or asthma medication use 30% 28% 26% 24% 22% 20% 18% 16% 14% 12% 10% 8% 6% 4% 2% 0% OR=0.81 p=0.41 72/ 398 61/ 377 OR=0.59 p=0.041 94/ 359 66/ 330 79/ 344 OR=0.51 p=0.015 OR=0.48 p=0.0061 OR=0.44 p=0.0026 YEAR 1 YEAR 2 YEAR 3 YEAR 4 YEAR 5 50/ 315 87/ 325 57/ 304 86/ 314 55/ 303 Placebo Grazax TREATMENT PERIOD FOLLOW-UP PERIOD

AIT for prevention of asthma: Which population? Results from the GAP study: Younger children had a higher predicted probability of developing asthma symptoms and asthma medication use than older children The risk reduction was independent of age The younger the children were at treatment-start, the greater the percentage was prevented from having asthma symptoms and asthma medication use during 2 years follow-up Halken S. PDS. EAACI 2017

Results - sensitization Prevention of new sensitization evidence that the risk of new sensitization was reduced over the short-term, but not confirmed in the prespecified sensitivity analysis: pooled RR=0.72; 95% CI 0.24 to 2.18 no evidence of any longer-term reduction in the risk of sensitization: pooled RR=0.47; 95% CI 0.08 to 2.77 A subgroup analysis showed a tendency towards an effect in children/adolescents after 3 yrs of AIT, supporting the rationale of the clinical effect Kristiansen M. PAI 2017 Halken S. PAI 2017

Results - sensitization Prevention of new sensitization Heterogeneity among the trials is considerable and there is a lack of good long-term studies to evaluate a possible preventive effect on the development of new allergic sensitizations sufficiently. There is currently no good evidence for a preventive effect of AIT for the development of new sensitizations, but some positive data suggest this topic as a relevant focus for future high quality trials Halken S. PAI 2017 Di Bona D. Allergy 2017 Di Lorenzo G. Int Forum Allergy Rhinol 2017

Conclusion AIT (SCIT & SLIT) can prevent the development of asthma in children/adolescents with pollen induced AR up to 2 yrs after discontinuation some new data indicate that a preventive effect on asthma symptoms and medication is maintained two yrs after discontinuation lack of good data for other allergens incl. HDM The evidence from RCTs is supported by: Controlled Before & After and Real World Life studies

Many gaps and important questions in the evidence Which is the best asthma outcome(s) for AIT studies? Which is the optimal age group, AR severity and duration for AIT for prevention? Which allergens apart from pollen? HDM? Which products, formulations and mode of administration Conclusion

Summary It remains to be demonstrated if there is an asthma preventive effect for children with milder AR Some may prefer AIT even for milder AR due to its symptom/medication reliefing effect, its longterm effect and possible asthma preventive effect Before initiating AIT the possible benefits, disadvantages, potential harms & costs and preferences should be discussed with the patient / family on an individual basis

Results Short-term prevention of allergic sensitization Random-effects meta-analysis of effectiveness of AIT, 2014

Results Short-term prevention of allergic sensitization Random-effects meta-analysis of effectiveness of AIT Pfifferi 2002: SCIT Parietaria 3 yrs Garcia 2010: SLIT peach 6 mos Marogna 2004: SLIT misc. 3 yrs Marogna 2008: SLIT misc. 3 yrs, 2014 Szephalusi 2014, SLIT grass/hdm Zolkipli 2015, oral HDM birch/grass 3 yrs

Results Long-term prevention of allergic sensitization Random-effects meta-analysis of effectiveness of AIT Author, year Dominicus, 2012 Limb, 2006 Song, 2016 Overall (I-squared = 92.9%, p 0.000) RR (95% CI) 0.60 (0.33, 0.93) 1.15 (0.00, 0.88) 0.12 (0.02, 2.76) 0.47 (0.08, 2.77) 0.0286 1 34.9

Results Long-term prevention of allergic sensitization Random-effects meta-analysis of effectiveness of AIT Author, year Dominicus, 2012 Limb, 2006 Song, 2016 Overall (I-squared = 92.9%, p 0.000) RR (95% CI) Dominicus: SCIT grass 2 yrs 0.60 (0.33, 0.93) Limb 2006: SCIT mix aero 2 yrs 1.15 (0.00, 0.88) Song, 2015: SCIT HDM 3 yrs 0.12 (0.02, 2.76) 0.47 (0.08, 2.77) 0.0286 1 34.9