Clinical Evaluation of Allergen Immunotherapy for Allergic Asthma

Abstract

Allergen immunotherapy (AIT) is the only available disease-modifying treatment for IgE-mediated allergic disease. Unlike conventional pharmacotherapy, AIT targets the underlying immune dysregulation driving allergic asthma (AA), with the potential to induce sustained off-treatment benefits. This narrative review examines the available evidence from both randomized controlled trials (RCTs) and real-world evidence to provide an updated and balanced overview of the clinical role of AIT in AA across different age groups. RCTs indicate that AIT can improve asthma symptom scores, reduce medication requirements and exacerbation risk, with additional steroid-sparing effects; however, findings are not consistent across trials. The strongest evidence is confined to house dust mite SLIT tablets, and the most recent Cochrane review judged the evidence insufficient for firm conclusions. Observational database studies enrolling up to 445,000 patients are consistent with these findings, reporting reductions in asthma events, medication use and treatment step-up, although their design precludes causal inference. Beyond symptomatic control, AIT has demonstrated a preventive role by interrupting the allergic trajectory, reducing the risk of new-onset asthma in patients with allergic rhinitis, and slowing progression to more severe asthma phenotypes. Long-term follow-up studies, mostly small and open in design, suggest that benefit may persist for up to 15 years after AIT discontinuation. Preliminary uncontrolled evidence also suggests that AIT may be feasible in selected patients with well-controlled severe asthma. In conclusion, AIT represents a uniquely positioned, disease-modifying strategy in the management of AA, with potential benefits spanning symptom control, prevention of disease onset and progression, and long-term benefits persisting after treatment discontinuation.

Introduction

Asthma is a chronic inflammatory disorder of the lower airways characterized by bronchial hyperresponsiveness, variable airflow obstruction, and airway remodeling.¹ It affects an estimated 262–350 million people worldwide and accounts for approximately 400,000–455,000 deaths annually, with a substantial economic burden and, in children, a marked impact on physical activity, school attendance, and quality of life (QoL).^1–5 Current management follows the stepwise Global Initiative for Asthma (GINA) approach, based on inhaled corticosteroids (ICS) combined with long-acting beta₂-agonists (LABA) and add-on controllers.⁶ These agents control symptoms and airway inflammation effectively but do not modify the underlying disease. Monoclonal antibody therapies targeting specific inflammatory pathways have transformed the management of severe asthma, eliminating exacerbations, maintenance oral corticosteroid (OCS) use and symptoms.^7–9 However, their long-term potential disease-modifying effects and the risk of symptom recurrence after discontinuation, remain undefined, particularly in children.

Allergic asthma (AA) is the phenotype driven by IgE-mediated sensitization to inhaled allergens; it is the most common asthma phenotype, typically beginning in childhood, and often coexisting with allergic rhinitis, with or without conjunctivitis (AR/C) and atopic dermatitis.¹⁰ It accounts for 70–80% of pediatric asthma, with a shift toward non-allergic phenotypes in adults.¹⁰ Sensitization (positive skin prick test/specific IgE) alone does not equal clinical allergy, since many sensitized individuals remain asymptomatic and diagnosis requires matching documented sensitization to a plausible symptom pattern on exposure.¹¹

Allergen immunotherapy (AIT) is currently the only available disease-modifying treatment for AR/C as it leads to¹² tolerance that reflects the induction of allergen-specific regulatory T and B cells, IgG4 blocking antibodies, and attenuation of Th2-driven inflammation.^12,13 It involves the repeated administration of the allergen to which the patient is sensitized in order to induce immunological tolerance,^13,14 and is delivered either subcutaneously (SCIT) or sublingually (SLIT).¹⁵ AIT consistently reduces symptom severity, symptomatic medication requirements and improves QoL,^16–20 and a treatment duration of at least three years is generally required for benefit to persist after discontinuation (“off-treatment” effect).²¹

Whether these effects extend to concomitant AA has become a question of direct clinical relevance. GINA now endorses house dust mite (HDM) SLIT as a therapeutic option in appropriately sensitized and symptomatic patients (with a forced expiratory volume in 1 second (FEV₁) >70% predicted), heralding a potential expansion of the role of AIT in the personalized management of AA.⁶ AA is a population of particular interest since HDM-sensitized asthma is associated with greater small airways dysfunction and airway hyperreactivity.²² AIT is an add-on, but never a substitute, for guideline-based controller therapy, indicted for patients with controlled asthma and preserved lung function; where uncontrolled or unstable disease is a contraindication.⁶ Latest European Academy of Allergy and Clinical Immunology (EAACI) guidelines on HDM-asthma treatment define HDM SLIT tablets as conditionally recommended (moderate-quality) in adults; and SCIT and pediatric SLIT drops conditionally (low-quality), both requiring careful patient selection.²³

Clinical evidence supports reductions in asthma symptoms and medication requirements, with additional effects on lung function and airway hyperreactivity.^18,24–26 AIT may also interrupt the allergic trajectory and may reduce progression from AR/C to new-onset asthma in sensitized children.^27–30 AIT is regarded as safe in appropriately selected patients, notably those with well-controlled asthma and preserved lung function.^30–32

This narrative review addresses a defined question: in patients with AA — or with AR/C and at risk of developing AA — does AIT deliver clinically meaningful and persistent benefit? Moreover in whom does this benefit occur, and which route and allergen is optimal? Previous reviews have largely focused on trial efficacy for a single route or allergen, or on immunological mechanisms. This review pairs randomized controlled trials (RCTs) and real-world evidence within each clinical domain, keeping levels of evidence explicit, rather than treating them separately. It spans the full AA trajectory rather than efficacy alone. It adopts an age-stratified lens, since benefit, magnitude and intervention timing differ across children, adolescents and adults. It incorporates post-guideline evidence, including the largest real-world cohorts to date. Together, these provide a practical, age-stratified picture of possible relationships between AIT for respiratory allergy and asthma and remaining evidence gaps.

Methodology and Evidence Framework and Hierarchy

A structured search of PubMed/MEDLINE, EMBASE, Scopus, and the Cochrane Library covered literature from January 2000 to July 2026, using terms including “asthma,” “allergen immunotherapy,” “symptoms,” “prognosis,” “clinical outcome,” “prevention,” “onset,” “off treatment,” and “corticosteroid-sparing.” RCTs, meta-analyses, and large real-world studies were prioritized, with relevant reviews and guidelines included for context. Given the heterogeneity of designs and endpoints, evidence was synthesized narratively. The level of evidence is kept explicit throughout. Within each domain, RCTs are presented first as the basis for efficacy claims; real-world evidence follows separately, informing effectiveness, generalizability, and durability beyond trial follow-up. RCTs are constrained by short duration; predominantly mild-to-moderate adult populations; non-standardized endpoints; and limited power for exacerbations, prompting EAACI proposed standardized outcomes.³³ Conversely, real-world studies remain vulnerable to confounding by indication, the healthy-adherer effect, residual confounding, reliance on prescription surrogates rather than verified diagnoses, and ascertainment bias. Accordingly, real-world findings are treated as supportive and hypothesis-strengthening rather than confirmatory, with effect sizes not interchangeable with RCT-derived estimates.

Allergen Immunotherapy and Reduction of Allergic Asthma Symptoms

Evidence from Clinical Trials

AIT has demonstrated possible clinical benefits in patients with mild-to-moderate AA. Four large RCTs including SLIT patients^18,25,34,35 and three including SCIT patients.^36–38 have been included in the present review.

A randomized double-blind placebo-controlled trial (RDBPCT) in 834 adults with HDM-induced AR/C plus HDM-induced asthma, demonstrated that both the 6 standardised quality (SQ) and 12 SQ HDM SLIT formulations significantly reduced the risk of moderate-to-severe asthma exacerbations compared with placebo during a period of ICS reduction, with no significant difference between the two active groups (hazard ratio [HR] 0.72 and 0.69 respectively, p < 0.05).²⁵ In contrast, a similarly designed RDBPCT by Tanaka et al in 826 Japanese adult patients with asthma insufficiently controlled by ICS found no significant difference between the 6 SQ, 12 SQ HDM, and placebo groups across all asthma outcomes, including exacerbation rate, ICS use, symptom scores, Asthma Control Questionnaire (ACQ), Asthma Quality of Life Questionnaire (AQLQ), and lung function.³⁴ A post hoc analysis of a subgroup accounting for approximately 40% of randomized subjects, those using short-acting beta₂-agonists (SABA) during the 14-day baseline period, suggested that the 20,000 Japanese allergen unit (equivalent to 6 SQ) HDM formulation may reduce asthma exacerbations compared with placebo, with only marginal statistical significance (p = 0.049).³⁴ The discrepancy between these two trials may be partly explained by differences in baseline asthma severity, as patients enrolled by Tanaka et al had relatively well-controlled disease compared to the more severe phenotype represented in the Virchow et al cohort.

Evidence for a steroid-sparing effect of HDM SLIT was provided by a further RDBPCT enrolling 604 subjects aged 14 years or older with mild-to-moderate HDM-driven asthma, in which the 6 SQ HDM formulation led to a significant mean reduction in daily ICS dose of 81 µg/day compared to placebo (p = 0.004).¹⁸ A post hoc analysis of a subset of this population, specifically those with a daily ICS dose of 400–800 µg and partially controlled asthma (ACQ score 1.0–1.5) at randomization, demonstrated a more pronounced treatment benefit in terms of ICS dose reduction.³⁹ After one year of treatment, this subgroup also reported statistically significant improvements in asthma-related QoL (AQLQ) and symptom control (ACQ) compared with placebo.³⁹ Conversely, an 18-month RDBPCT by Pham-Thi et al in 111 children aged 5–15 years evaluating 300 index of reactivity (IR) HDM SLIT found no significant differences compared with placebo in ICS or SABA use, asthma symptom scores (ASS), lung function, or rhinitis symptom scores.³⁵

Regarding HDM SCIT, two placebo-controlled trials using depigmented polymerized extracts provided early supportive evidence. Ameal et al,³⁷ in 55 patients with HDM-induced AR/C and mild-to-moderate asthma treated with D. pteronyssinus SCIT, reported significant improvements after one year in bronchial provocation test results and in symptom and medication scores (p < 0.001), with 78% and 68% reductions in symptoms and medication use respectively compared with placebo. Garcia-Robaina et al,³⁸ using a mixed D. pteronyssinus/D. farinae depigmented polymerized extract in 64 patients with a similar phenotype, likewise reported significant improvement in bronchial provocation testing at one year (p < 0.001), alongside a 48% greater reduction in bronchial symptom scores and a 50% greater reduction in ICS consumption compared with placebo (p < 0.001 for both), with significantly more ICS-free weeks in the active group (p < 0.001). More recently, Jutel et al,³⁶ in a dose-ranging RDBPCT enrolling 146 Polish and Spanish patients with controlled HDM-induced asthma, demonstrated that after approximately 7 months of treatment, a significant reduction in the minimal ICS dose required for asthma control was observed only with the highest dose tested (18,000 therapeutic units (TU); p < 0.05), with 85% of patients in this group achieving complete ICS discontinuation compared with 40% on placebo (p < 0.05).

While the available evidence suggests clinically meaningful benefits of AIT (particularly HDM SLIT) in reducing asthma symptoms, medication requirements, and exacerbation frequency, the most recent Cochrane systematic review concluded that evidence remains insufficient to draw firm conclusions, largely due to the predominance of studies enrolling patients with mild asthma and the limited number of trials reporting exacerbation frequency as a primary outcome.⁴⁰ However, the most recent meta-analysis that included 29 RCTs concluded that SCIT showed greater efficacy than SLIT specifically in reducing medication scores (standardised mean difference [SMD] −2.21 for SCIT vs −1.68 for SLIT).⁴¹

For this reason, when considering AIT for the treatment of AA, the product-specific individual evaluation with corresponding proof of efficacy and safety in clinical studies is therefore of central importance.²⁹

Evidence from Real World Data

Real-world data collected from retrospective database analyses support the potential beneficial effects of AIT in AA symptoms.^27,42–49

Real-world data from the EfficAPSI study, a nationwide French cohort of over 445,000 patients, reported that SLIT was associated with a 36% overall reduction in new asthma events, with greater reductions observed in younger patients and children, and consistent effects across multiple allergens including birch (55%), grass (44%), ragweed (48%), and HDM (37%).⁴⁷ In another real-world population-based Danish study comparing patients with asthma who received an AIT prescription with those who did not, a sustained reduction in exacerbation rate was observed in the 3 years following completion of AIT, on average 74% in patients with seasonal allergies and 57% in those with HDM allergy, compared with non-AIT patients.⁴⁵ Further evidence comes from a large German database study by Fritzsching et al,⁴⁶ which examined 92,048 subjects with AR/C with or without pre-existing asthma (46,024 having received AIT with SLIT drops or tablets or SCIT, matched 1:1 with controls; mean age 30 years). In subjects with pre-existing asthma, AIT was associated with a significantly greater reduction in asthma prescriptions compared with controls at both 3 and 5 years of follow-up, driven primarily by reductions in SABA and ICS/LABA prescriptions (p < 0.01 to 0.0001); AIT-treated patients also showed a significantly greater likelihood of stepping down asthma treatment (p < 0.0001), and from 2 to 8 years of follow-up, the risk of severe asthma exacerbations was significantly lower in the AIT group (p < 0.05 to 0.0001).⁴⁶

Regarding SCIT specifically, Jutel et al,⁴² in a German cohort of 3,568 subjects aged 5 to 70 years with HDM-driven disease (892 having received SCIT and 2,676 matched controls), reported that over up to 6 years of follow-up, asthma prescriptions were significantly reduced by approximately 40% in AIT-treated patients compared with controls (p < 0.001), consistently in both children and adolescents (p < 0.01) and adults (p < 0.05). Similarly, Vogelberg et al,⁴³ examining 11,918 subjects aged 5 to 65 years receiving grass or tree pollen SCIT with allergoids (5,959 AIT vs 5,959 matched controls) over a median follow-up of 6.3 years, found that among subjects with pre-existing asthma, the proportion receiving anti-asthmatic medication was significantly reduced by 14–16% in the AIT group compared with controls (odds ratio [OR] ~0.5; p < 0.001 in all cases), with the reduction in asthma prescriptions during follow-up versus baseline being significantly greater by 29% in AIT-treated patients (p < 0.001). A Korean real-world study by Rhyou et al,⁴⁴ in 117 subjects aged 18 years or older with AA (48 having received SCIT with HDM, tree or weed pollens, cat or dog dander, or combinations thereof, and 69 controls) further demonstrated a significantly greater proportion of patients reducing or discontinuing ICS use in the AIT group at 6 months (52% vs 24%; p < 0.05), 1 year (71% vs 35%; p < 0.01), 2 years (89% vs 36%; p < 0.001), and 3 years (96% vs 51%; p < 0.001) after treatment initiation; the proportion of patients experiencing acute asthma exacerbations during the first year was also significantly lower in the AIT group (8% vs 28%; p < 0.05).

Dedicated pediatric real-world evidence was provided by Woehlk et al,²⁷ who conducted a large-scale analysis of 11,036 children under 18 years with physician-diagnosed AR/C, with or without pre-existing asthma, matched 1:1 to non-AIT controls and followed over 9 years within the framework of the REACT study. In children with pre-existing asthma, AIT was associated with additional reductions in asthma medication use (−21% beyond −48% in controls), severe exacerbations (−21% beyond −36%), and new oral corticosteroid prescriptions (−33% beyond −41%), with more pronounced benefits observed in younger children (0–11 years) compared with adolescents (12–17 years), suggesting a disease-modifying effect and supporting the importance of early intervention.

Another real-world study from France, including 950 children younger than 12, showed that, in the subgroup of 295 asthmatic children treated with SLIT and assessed through the Asthma Control Test (ACT), the proportion with controlled asthma increased from 77.1% at baseline to 83.3% after 12–15 months of AIT.⁵⁰

Additional SLIT-specific evidence emerged from a retrospective study conducted in China, in which six months of pre-seasonal mugwort SLIT significantly improved daytime and nighttime symptoms, increased ACT scores, and improved FEV₁ by approximately 103 mL compared with placebo.⁵¹

With respect to mould allergy, low-quality evidence supports the use of SCIT with Alternaria for asthma, while very low-quality evidence exists for SCIT with Cladosporium and SLIT with Alternaria.⁵²

The principal clinical trials and real-world studies evaluating the effects of AIT on asthma-related clinical outcomes are summarized in Table 1.

Table 1.

Selected Clinical Trials and Real-World Studies Evaluating AIT for Asthma Related Clinical Outcomes

Study	Design	Population	Intervention and Comparator	Key Clinical Outcomes
Randomized clinical trials
Virchow et al,25	Multicentre RDBPCT	834 adults (17–83 years) with HDM-induced AR/C and inadequately controlled asthma	HDM SLIT tablet, 6 or 12 SQ-HDM vs placebo; 13–18 months with final ICS reduction/withdrawal	Both 6 and 12 SQ-HDM reduced moderate-to-severe exacerbations versus placebo during ICS reduction (HR 0.72 and 0.69, respectively; p<0.05), with no significant difference between the active doses
Tanaka et al,34	Multicentre RDBPCT	826 adults (18–64 years) with HDM-induced asthma insufficiently controlled by ICS	HDM SLIT tablet, 6 or 12 SQ-HDM vs placebo; 13–19 months	No significant differences across asthma outcomes in the overall population; a post hoc subgroup using SABA at baseline showed a marginal reduction in exacerbations with 6 SQ-HDM (p=0.049)
Mosbech et al; de Blay et al,18,39	Multicentre RDBPCT plus post hoc analysis	604 patients aged ≥14 years with mild-to-moderate HDM-driven asthma requiring ICS	HDM SLIT tablet, 1, 3 or 6 SQ-HDM vs placebo; 1 year	6 SQ-HDM reduced daily ICS dose by 81 micrograms/day versus placebo (p=0.004); the effect was greater in partially controlled patients receiving 400–800 micrograms/day ICS, with improved AQLQ and ACQ
Pham-Thi et al,35	RDBPCT	111 children (5–15 years) with pharmacologically controlled HDM-induced asthma	HDM SLIT, 300 IR vs placebo; 18 months	No significant differences versus placebo in ICS or SABA use, asthma symptom scores, lung function, or rhinitis symptom scores
Ameal et al,37	RDBPCT	55 patients (14–48 years) with HDM-induced AR/C and mild-to-moderate asthma	Depigmented polymerized D. pteronyssinus SCIT vs placebo; 12 months	Improved bronchial provocation test results; symptom and medication use fell by 78% and 68%, respectively, versus placebo (p<0.001)
Garcia-Robaina et al,38	RDBPCT	64 adults (mean age 37 years) with HDM-induced AR/C and mild-to-moderate asthma	Depigmented polymerized D. pteronyssinus/D. farinae SCIT vs placebo; 12 months	Improved bronchial provocation testing; bronchial symptoms and ICS use decreased 48% and 50% more than with placebo, with more ICS-free weeks (all p<0.001)
Jutel et al,36	Dose-ranging RDBPCT	146 adults (18–40 years) with controlled HDM-induced asthma	D. pteronyssinus allergoid SCIT, 2,000–18,000 TU vs placebo; about 7 months	Only 18,000 TU significantly reduced the minimal ICS dose required for control; 85% discontinued ICS versus 40% with placebo (p<0.05)
Real-world studies
Demoly et al,47	Nationwide retrospective cohort	445,574 patients aged ≥5 years with AR, with or without asthma	Seasonal/perennial SLIT vs untreated controls; up to about 8 years	36% overall reduction in new asthma events; reductions were greater in younger patients and children and were observed for birch (55%), grass (44%), ragweed (48%), and HDM (37%)
Woehlk et al,45	Nationwide register study	2,688 adults (18–44 years) with seasonal or perennial allergic asthma	HDM, birch and/or grass SCIT or SLIT; ≥3 years treatment plus 3 years observation	Sustained reduction in exacerbation rate during the 3 years after AIT completion: 74% in seasonal allergy and 57% in HDM allergy versus patients without an AIT prescription
Fritzsching et al,46	Nationwide matched retrospective cohort	92,048 patients (mean age 30 years) with AR, with or without asthma	Predominantly pollen or HDM SCIT/SLIT vs matched controls; 2–8 years	In patients with pre-existing asthma, asthma prescriptions decreased more at 3 and 5 years, treatment step-down was more likely, and severe-exacerbation risk was lower over years 2–8 versus controls
Jutel et al,42	Nationwide matched retrospective cohort	3,568 patients (5–70 years) with HDM-driven allergic disease	HDM SCIT vs matched controls; follow-up up to 6 years	Asthma prescriptions decreased by approximately 40% versus controls (p<0.001), consistently in children and adolescents and in adults
Vogelberg et al,43	Nationwide matched retrospective cohort	11,918 patients (5–65 years) with grass/tree-pollen allergy	Pollen allergoid SCIT vs matched controls; median follow-up 6.3 years	Among patients with pre-existing asthma, anti-asthmatic medication use was 14–16% lower (OR approximately 0.5; p<0.001), and the reduction in prescriptions was 29% greater than in controls
Rhyou et al,44	Retrospective cohort	117 adults with allergic asthma	SCIT vs pharmacotherapy alone; outcomes to 3 years	ICS reduction or discontinuation was more frequent with AIT at 6 months and at 1, 2, and 3 years; first-year exacerbations occurred in 8% versus 28% of controls (p<0.05)
Woehlk et al,27	Pediatric matched REACT cohort	11,036 patients <18 years with AR, with or without asthma	Seasonal/perennial SCIT or SLIT vs matched controls; 9 years	In children with pre-existing asthma, AIT produced additional reductions in medication use (21%), severe exacerbations (21%), and new oral-corticosteroid prescriptions (33%); benefits were greater at ages 0–11 years
Caimmi et al,50	Prospective multicentre observational cohort	4,794 SLIT initiators (950 children; 3,844 adolescents/adults) with respiratory allergy	Liquid named-patient-product SLIT; 12–15 months	Among 295 asthmatic children treated with SLIT, controlled asthma increased from 77.1% at baseline to 83.3% after 12–15 months
Zhao et al,51	Retrospective controlled study	60 patients with mild-to-moderate mugwort-induced asthma	Preseasonal Artemisia annua SLIT vs symptomatic therapy; ≥6 months	Six months of preseasonal mugwort SLIT improved daytime and nighttime symptoms and ACT scores, and increased FEV1 by approximately 103 mL versus placebo

Abbreviations: ACT, Asthma Control Test; AIT, allergen immunotherapy; AR, allergic rhinitis; AR/C, allergic rhinitis with or without conjunctivitis; FEV₁, forced expiratory volume in 1 second; HDM, house dust mite; HR, hazard ratio; ICS, inhaled corticosteroid; IR, index of reactivity; OR, odds ratio; RDBPCT, randomized double-blind placebo-controlled trial; REACT, Real-world Effectiveness of Allergy Immunotherapy; SCIT, subcutaneous immunotherapy; SLIT, sublingual immunotherapy; SQ, standardized quality; TU, therapeutic units; vs, versus.

AIT in the Prevention of the Onset and Worsening of Allergic Asthma

AR/C and asthma are closely associated conditions, sharing a common pathophysiological basis rooted in T helper 2 (Th2)-skewed immune dysregulation.⁵³ This biological continuum supports the concept of “respiratory allergy” as a unified disease process, as encapsulated by the so-called “united airway disease” hypothesis or “unified airway model”.^53–55 Epidemiological data consistently demonstrate that individuals with AR/C and in particular children, are at significantly increased risk of developing asthma over time, with affected patients carrying a two- to sevenfold greater risk compared to non-sensitized individuals.^56–58 Perennial AR/C, in particular, is associated with extension of eosinophilic inflammation to the lower airways, and bronchial hyperresponsiveness represents an additional risk factor amplifying the likelihood of asthma development.^59–61 Given that AIT targets the underlying Th2-driven immune response shared across both conditions, it is uniquely positioned to halt or at least attenuate the progression from AR/C to AA.⁶² AIT plays a critical role in secondary prevention, particularly in interrupting the allergic trajectories in children with AR/C suggesting that there could be a “window of opportunity” in early childhood during which AIT may pivotally influence the trajectory of allergic disease progression.⁶³ Furthermore, as uncontrolled AR/C may itself contribute to the worsening of coexisting asthma, effective treatment of upper airway disease through AIT may confer additional benefits on lower airway control.

AIT and Prevention of Allergic Asthma Onset

Evidence from Clinical Trials

The earliest evidence dates to a trial conducted in 1954, which followed 200 patients over the age of ten with grass pollen-induced AR/C, with or without concomitant asthma. Of the 143 participants who were asthma-free at baseline, only three developed asthma during the co-seasonal SCIT treatment period, all of whom had been allocated to the placebo arm.⁶⁴ In the decades that followed, further studies assessed the asthma-preventive potential of SCIT^65–72 and SLIT,^73–75 encompassing a range of designs including open uncontrolled trials, open RCTs, and RDBPCTs. In an open, uncontrolled trial involving 36 adolescent and adult patients, Jacobsen et al,⁷¹ reported that none of the participants without asthma at baseline developed the disease during the 6 years following completion of a 3-year course of birch SCIT. Following that, Grembiale et al,⁷⁰ reported in a RDBPCT that included 44 pediatric and adult patients monosensitized to HDM that 2 years after HDM-SCIT 0 patients of the treated group developed asthma compared with 2 in the placebo group, although statistical significance was not reached likely due to underpowering (p = 0.49). In the PAT RCT that included 205 European children aged from 6 to 14 years, after 3 years of grass and/or birch SCIT for children without asthma at baseline, the OR for no development of asthma was 2.5 in favour of AIT (p < 0.05)⁶⁷ and the preventive effect of SCIT against asthma was maintained 2 years (OR 2.7; p < 0.05) and 7 years (OR 2.5; p < 0.05) after treatment discontinuation.^65,66 Subsequently in a RDBPCT conducted by Polosa et al,⁶⁹ in non-asthmatic adult patients monosensitized to pellitory pollen, following 3 years of Parietaria SCIT, 2/14 patients of the treated group developed asthma compared with 7/15 in the placebo group (p = 0.06). Finally, for SCIT, Peng et al,⁷² reported the findings of an open controlled trial involving 146 Chinese children, adolescents, and adults, in which a 3-year course of HDM SCIT followed by 2 years of follow-up was associated with a significantly reduced risk of asthma development among patients who were asthma-free at baseline, with an OR of 3.6 in favour of the SCIT group (p < 0.05).

Regarding SLIT, the first open RCT was conducted by Novembre et al,⁷³ on 113 children with grass-pollen induced AR/C and demonstrated that after 3 years of co-seasonal grass pollen SLIT, the proportion of patients having developed asthma was significantly lower in the treated subjects compared with the control subjects (p < 0.05). Following that, Marogna et al,⁷⁴ showed in an open RCT conducted on children with AR/C with or without asthma that after 3 years of HDM/grass/birch or Parietaria SLIT only 2% of treated subjects had mild asthma compared with 29% of control subjects (p < 0.0001). Finally, the most rigorously designed study addressing this question was the GAP RDBPCT that, although did not meet its primary endpoint (a statistically significant difference in time to asthma onset between the active and placebo groups), demonstrated that SLIT significantly reduced the risk of developing asthma symptoms or requiring asthma pharmacotherapy among those who did develop the condition (OR 0.66; p < 0.05), an effect that was consistent across both the two-year follow-up period and the full five-year study duration.⁷⁵

Taken together, the findings consistently suggest that AIT not only reduces the likelihood of asthma development in patients with AR/C, but that this preventive effect may persist for years following treatment discontinuation.⁷⁶ Statistically significant prevention of asthma onset and maintenance of this effect were reported in four clinical trials, all of which were open controlled studies, three of which incorporated randomization, and which employed either subcutaneous or sublingual administration of HDM or pollen extracts.^66,67,73,74

Evidence from Real World Data

Data from the real-world, that allowed the observation of larger more inclusive populations as well as longer periods of observation,^77,78 supported data from RCTs and RDBPCTs. Nine studies have been reported in the literature as addressing the preventive effect of AIT in asthma development.^{42,43,47,79–85}

Schmitt et al,⁷⁹ reported findings from a German cohort study comparing adult patients treated with seasonal or perennial SCIT or SLIT against untreated controls. At 6 years from study initiation, patients receiving SCIT demonstrated a significantly lower risk of developing asthma compared with controls (relative risk [RR] 0.57; p = 0.005), whereas the effects of SLIT drops (RR 0.43, p = 0.14) and combinations of SCIT and SLIT (RR 1.22, p = 0.65) did not reach statistical significance. Wahn et al,⁸⁰ conducted a retrospective analysis of a German prescription database, comparing patients receiving at least two seasonal AIT cycles (SLIT or SCIT, natural extracts or allergoids) with matched non-AIT controls. During treatment, new-onset asthma risk was significantly reduced in the AIT group (OR 0.83; p = 0.001), although this effect was driven mainly by SLIT natural extracts and one SCIT allergoid preparation. Over the full 8-year period, however, no significant overall reduction was observed (OR 0.94; p = 0.16), with a significant protective effect persisting only for SLIT natural extracts (OR 0.69; p < 0.0001). Further nationwide database studies have substantiated these findings across multiple allergens and treatment modalities. Devillier et al,⁸¹ and Zielen et al,⁸² analyzed a German cohort of 74,126 subjects receiving grass pollen SLIT tablets (2,851 AIT vs 71,275 matched controls), finding a significantly lower 7-year asthma risk with AIT (OR 0.70; p < 0.01), including among patients who remained asthma-free at treatment completion (p < 0.01). A parallel French analysis by Devillier et al,⁸³ in 28,574 subjects (1,099 AIT vs 27,475 controls) similarly showed a significantly reduced asthma risk across the treatment, 1- to 2-year follow-up, and 5-year full analysis periods (OR 0.36–0.63; p < 0.0001 to 0.01).

Jutel et al,⁸⁴ reported comparable findings with HDM SCIT with allergoids in 67,090 German subjects (2,350 AIT vs 64,740 controls), showing a significantly reduced 9-year asthma risk (OR 0.81 p < 0.01). In the largest cohort of patients reported in the EfficAPSI study, a French cohort of 445,574 subjects receiving seasonal or perennial SLIT drops (Devillier et al,⁸⁵ Demoly et al,⁴⁷,112,492 AIT vs 333,082 controls) a significant 23–38% reduction in asthma risk was demonstrated over 8 years (HR 0.77–0.62), which was consistent across age groups and allergens except cat.

Finally, Jutel et al,⁴² and Vogelberg et al,⁴³ reported significant reductions in asthma or asthma-medication risk with HDM SCIT (3,568 subjects; OR 0.73; p < 0.05) and grass/tree pollen SCIT with allergoids (11,918 subjects; OR 0.77; p = 0.001), respectively, both also demonstrating a significantly prolonged time to asthma onset in AIT-treated patients.

Overall, evidence from real world data and registries supported RCTs and RDBPCTs results, adding consistency on those data.

The main clinical trials and real-world studies evaluating the preventive effect of AIT on asthma onset are summarised in Table 2.

Table 2.

Selected Clinical Trials and Real-World Studies Evaluating AIT for Prevention of Asthma Onset

Study	Design	Population	Intervention and Comparator	Key Clinical Outcomes
Clinical trials
Frankland et al,64	Placebo-controlled trial	200 patients >10 years with grass-pollen AR, with or without asthma	Co-seasonal grass-pollen SCIT vs placebo	Among 143 participants without asthma at baseline, three developed asthma during treatment, all in the placebo arm
Jacobsen et al,71	Open uncontrolled prospective study	36 patients (15–72 years) with tree-pollen rhinoconjunctivitis, with or without asthma	Birch ± alder/hazel SCIT for 3 years; 6-year post-treatment follow-up	No participant without asthma at baseline developed asthma during the 6 years after completing 3 years of birch SCIT
Grembiale et al,70	RDBPCT	44 patients (10–38 years) with HDM rhinitis and bronchial hyperresponsiveness	HDM SCIT vs placebo for 2 years	Asthma developed in 0 SCIT versus 2 placebo recipients; the difference was not significant (p=0.49)
Jacobsen et al; Niggemann et al; Möller et al,65–67	Open RCT with long-term follow-up	205 children (6–14 years) with grass/birch rhinoconjunctivitis, with or without mild asthma	Pollen SCIT vs pharmacotherapy for 3 years; follow-up at 2 and 7 years	Odds of remaining asthma-free favored SCIT after 3 years (OR 2.5), and 2 years (OR 2.7) and 7 years (OR 2.5) after discontinuation (all p<0.05)
Crimi et al; Polosa et al,68,69	RDBPCT	30 adults randomized; 29 analyzed (14 SCIT, 15 placebo), all non-asthmatic with Parietaria rhinitis	Parietaria judaica SCIT vs placebo for 3 years	After 3 years, asthma developed in 2/14 SCIT versus 7/15 placebo recipients; the difference did not reach significance (p=0.06)
Peng et al,72	Open controlled trial	146 patients aged ≥5 years with HDM-induced AR, with or without asthma	HDM SCIT vs pharmacotherapy for 3 years; 2-year follow-up	Among participants without asthma at baseline, asthma development was less likely with SCIT (OR 3.6 in favor of SCIT; p<0.05)
Novembre et al,73	Open RCT	113 children (5–14 years) with grass-pollen rhinoconjunctivitis	Co-seasonal grass-pollen SLIT vs pharmacotherapy for 3 years	After 3 years, asthma development was significantly lower with SLIT than with control treatment (p<0.05)
Marogna et al,74	Open RCT	216 children/adolescents (5–17 years) with AR, with or without intermittent asthma	HDM or pollen SLIT plus pharmacotherapy vs pharmacotherapy for 3 years	After 3 years, mild asthma was present in 2% of SLIT-treated participants versus 29% of controls (p<0.0001)
Valovirta et al,75	Multicentre RDBPCT	812 children (5–12 years) with grass-pollen rhinoconjunctivitis and no asthma	SQ grass SLIT tablet vs placebo for 3 years; 2-year blinded follow-up	The primary time-to-asthma endpoint was not met; SLIT reduced asthma symptoms or asthma-pharmacotherapy use among those who developed asthma (OR 0.66; p<0.05), consistently through 5 years
Real-world studies
Schmitt et al,79	Retrospective population cohort	118,754 adults with AR and no asthma	Seasonal/perennial SCIT, SLIT or combined therapy vs untreated controls; about 6 years	New-onset asthma risk was lower with SCIT (RR 0.57; p=0.005); effects of SLIT drops (RR 0.43; p=0.14) and combined SCIT/SLIT (RR 1.22; p=0.65) were not significant
Wahn et al,80	Nationwide prescription-database study	54,006 patients aged ≥5 years with birch-family pollen allergy	Natural-extract/allergoid SCIT or SLIT vs matched controls; about 8 years	Asthma onset was lower during treatment (OR 0.83; p=0.001), but not over the full 8 years (OR 0.94; p=0.16); benefit persisted only for natural-extract SLIT (OR 0.69; p<0.0001)
Devillier et al; Zielen et al,81,82	Nationwide retrospective database study	74,126 patients aged ≥5 years receiving grass SLIT tablets or control therapy	Grass SLIT tablets vs matched controls; 7 years	Seven-year asthma risk was lower with grass SLIT tablets (OR 0.70; p<0.01), including among patients who were asthma-free at treatment completion
Devillier et al,83	Retrospective database study	28,574 patients aged ≥5 years receiving grass SLIT tablets or controls	Grass SLIT tablets vs nasal-corticosteroid controls; about 5 years	Asthma risk was lower during treatment, the 1- to 2-year follow-up, and the full 5-year period (OR 0.36–0.63; p<0.0001 to p<0.01)
Jutel et al,84	Nationwide retrospective cohort	67,090 patients (5–50 years) with HDM-induced allergic disease	HDM allergoid SCIT vs untreated controls; about 9 years	Nine-year asthma risk was lower with HDM SCIT (OR 0.81; p<0.01)
Demoly et al; Devillier et al,47,85	Nationwide retrospective cohort	445,574 patients aged ≥5 years with AR	Seasonal/perennial SLIT vs untreated controls; about 8 years	Asthma risk was reduced by 23–38% over 8 years (HR 0.77–0.62), consistently across age groups and allergens except cat
Jutel et al,42	Nationwide matched retrospective cohort	3,568 patients (5–70 years) with HDM-driven allergic disease	HDM SCIT vs matched controls; follow-up up to 6 years	Asthma risk was lower with HDM SCIT (OR 0.73; p<0.05), and time to asthma onset was prolonged
Vogelberg et al,43	Nationwide matched retrospective cohort	11,918 patients (5–65 years) with grass/tree-pollen allergy	Pollen allergoid SCIT vs matched controls; median 6.3 years	Asthma-medication initiation risk was lower (OR 0.77; p=0.001), and time to onset was prolonged

Abbreviations: AIT, allergen immunotherapy; AR, allergic rhinitis; HDM, house dust mite; HR, hazard ratio; OR, odds ratio; RCT, randomized controlled trial; RDBPCT, randomized double-blind placebo-controlled trial; RR, relative risk; SCIT, subcutaneous immunotherapy; SLIT, sublingual immunotherapy; SQ, standardized quality; vs, versus.

AIT and Prevention of Allergic Asthma Worsening

Beyond reducing the risk of asthma onset, AIT may also slow the progression of established asthma from milder to more severe phenotypes. It should be emphasised that, unlike the evidence on asthma onset, this evidence derives exclusively from observational real-world studies, with no RCTs to date having addressed asthma progression as an endpoint.^47,82–86

Zielen et al,⁸² and Devillier et al,⁸³ in the German and French grass pollen SLIT tablet cohorts described above, reported that asthma progression (assessed by prescriptions for symptomatic asthma medication) was significantly slower in AIT-treated patients compared with controls, both during treatment and over the full follow-up period (p < 0.01 to p < 0.0001). Notably, the two studies^82,83 reported that this protective association persisted beyond treatment discontinuation. Devillier et al,⁸³ reported that the slowing of asthma progression with SLIT was more pronounced during the post-treatment follow-up period than during active treatment (a 40% vs ≤10% reduction in symptomatic asthma medication prescriptions, respectively), suggesting a partly delayed benefit that may reflect an AIT-induced long-term reversal of the underlying Th2-skewed immune response and associated specific IgE production.

This durable preventive effect on asthma progression after treatment cessation was further confirmed by two additional studies. Jutel et al,⁸⁴ in their HDM SCIT cohort, reported an 11% overall reduction in asthma prescriptions, rising to 39% in the pediatric subgroup (p < 0.001), while Schmitt et al,⁸⁶ assessing progression across GINA treatment steps in 39,167 subjects, found significantly reduced risk of progression from step 1 to step 3 (HR 0.87) and step 3 to step 4 (HR 0.66), with the preventive effect strongest in adolescents (HR 0.72) and absent in patients aged 50 or older (HR 1.09). Taken together, these findings suggest that the protective effect of AIT on asthma progression may be more pronounced in younger patients.

Finally, in the EfficAPSI cohort of 445,574 subjects receiving seasonal or perennial SLIT, a significant ~30% reduction in the risk of asthma treatment step-up over an 8-year period (HR ~0.7) had been reported, an effect consistent across age groups and irrespective of whether the allergen source was HDM or grass pollen.⁴⁷

The principal real-world studies evaluating the effect of AIT on asthma worsening are summarised in Table 3.

Table 3.

Selected Real-World Studies Evaluating AIT for Prevention of Asthma Worsening

Study	Design	Population	Intervention and Comparator	Key Clinical Outcomes
Zielen et al,82	Nationwide retrospective database study	74,126 patients aged ≥5 years receiving grass SLIT tablets or control therapy	Grass SLIT tablets vs matched controls; 7 years	Asthma progression, assessed through symptomatic-asthma medication prescriptions, was slower during treatment and over the full follow-up; the association persisted after treatment discontinuation
Devillier et al,83	Retrospective database study	28,574 patients aged ≥5 years receiving grass SLIT tablets or controls	Grass SLIT tablets vs nasal-corticosteroid controls; about 5 years	Asthma progression was slower during treatment and over the full follow-up, with a larger reduction in symptomatic medication prescriptions after treatment than during treatment (40% versus 10% or less)
Demoly et al; Devillier et al,47,85	Nationwide retrospective cohort	445,574 patients aged ≥5 years with AR	Seasonal/perennial SLIT vs untreated controls; about 8 years	Asthma-treatment step-up risk was reduced by approximately 30% over 8 years (HR approximately 0.7), consistently across age groups and for HDM and grass pollen
Jutel et al,84	Nationwide retrospective cohort	67,090 patients (5–50 years) with HDM-induced allergic disease	HDM allergoid SCIT vs untreated controls; follow-up up to 6 years	Asthma prescriptions decreased by 11% overall and by 39% in the pediatric subgroup (p<0.001)
Schmitt et al,86	Population-based retrospective cohort	39,167 patients aged ≥12 years with asthma	AIT vs no AIT; follow-up up to 8 years	Progression risk was lower from GINA step 1 to 3 (HR 0.87) and step 3 to 4 (HR 0.66); the effect was strongest in adolescents (HR 0.72) and absent at age 50 years or older (HR 1.09)

Abbreviations: AIT, allergen immunotherapy; AR, allergic rhinitis; GINA, Global Initiative for Asthma; HDM, house dust mite; HR, hazard ratio; SCIT, subcutaneous immunotherapy; SLIT, sublingual immunotherapy; vs, versus.

AIT and “Off Treatments” Effects

A defining and clinically important feature of AIT, distinguishing it from conventional pharmacotherapy, is its capacity to induce sustained clinical benefit that persists beyond treatment discontinuation, the so-called “off-treatment” effect.

Evidence for this property in the context of AA has accumulated across both SLIT and SCIT, and across varying treatment durations and patient populations. Marogna et al,⁸⁷ in a prospective open controlled study following 78 adult patients with HDM-induced AR/C with or without asthma over 15 years, demonstrated that the clinical benefit of mite SLIT, assessed through combined symptom and medication scores, bronchial hyperreactivity, and nasal eosinophil counts, persisted for 7 years after a 3-year course and for 8 years after courses of 4 or 5 years, with a 4-year duration identified as the optimal treatment length.⁸⁷ Notably, the long-lasting benefit extended beyond symptom control to include objective parameters of airway inflammation and bronchial responsiveness, and new allergen sensitizations developed in fewer than 25% of SLIT-treated patients compared with all control subjects over the 15-year observation period.

Furthermore, a second course of SLIT, initiated once the clinical benefit had attenuated, achieved a more rapid and pronounced response than the first course.

Regarding SCIT, Tang et al,⁸⁸ reported a retrospective cohort study of 46 Chinese children aged 5–14 years with HDM-sensitized AA who had completed a 3-year standardized HDM SCIT course. Significant improvements from baseline in ASS, rhinitis symptom scores (RSS), total symptom scores (TSS), visual analog scale (VAS), Pediatric Asthma Quality of Life Questionnaire (PAQLQ), and ACQ were observed at the end of treatment and sustained at 7, 10, and 15 years of post-treatment follow-up (all p < 0.001), with no significant difference in outcomes between monosensitized and polysensitized children.⁸⁸

Finally, the SAGITAL study, a real-world retrospective multicenter study conducted across 16 Spanish centers in 93 patients aged 6 years or older with well-controlled severe AA receiving AIT (predominantly SCIT, 91.4%), provided further evidence of durable clinical benefit in a more challenging patient population.⁸⁹ After AIT initiation, significant improvements were observed in fractional exhaled nitric oxide (FeNO) at 6 months (p = 0.049) and in FEV₁ at 12 months (p = 0.028), alongside a significant reduction in rescue medication use (p = 0.019) and a 75.8% reduction in emergency department visits. All 15 patients receiving concomitant monoclonal antibody therapy (predominantly omalizumab) at baseline were free of monoclonal antibodies after 5 years of AIT. This observation is hypothesis-generating due to the nature of the study (retrospective and uncontrolled), so the contribution of AIT cannot be separated from that of the biologic itself or from spontaneous improvement, and controlled trials are required before AIT can be proposed as a means of withdrawing monoclonal antibody therapy.⁸⁹

Discussion

The evidence reviewed supports a role for AIT across four domains of AA management, but strength of evidence differs materially between them (Figure 1). It is strongest for symptom and medication control in HDM-driven disease, whereby RDBPCTs in adolescents and adults show a steroid-sparing effect and fewer moderate-to-severe exacerbations during ICS reduction, consistent with GINA’s endorsement of HDM SLIT in sensitized, symptomatic patients. Strength of evidence is reasonable for prevention of new-onset asthma in AR/C, supported by concordant randomized and real-world data with therapeutic effects persisting after discontinuation, although the largest and most rigorous trial missed its primary endpoint. Strength of evidence is weaker for prevention of progression to more severe asthma and for durability beyond a decade. Finally, evidence is preliminary, from a single uncontrolled study, for AIT in well-controlled severe asthma on biologics.

Figure 1.

Allergen immunotherapy across the allergic asthma continuum. Allergen immunotherapy (AIT) may improve asthma control, prevent asthma onset, and slow disease progression, with sustained post-treatment effects mediated by allergen-specific immune tolerance. Created with Biorender.com.

Abbreviations: GINA, Global Initiative for Asthma; HDM, house dust mite; ICS, inhaled corticosteroid; IgG4, immunoglobulin G4; SCIT, subcutaneous immunotherapy; SLIT, sublingual immunotherapy; Th2, T helper 2.

The two evidence streams have complementary rather than overlapping weaknesses: RCTs are internally valid but confined to mild-to-moderate, predominantly adult populations, short treatment periods and heterogeneous endpoints, while real-world evidence is large, longitudinal and generalizable but observational, reliant on prescription-based surrogates, and unable to exclude confounding by indication or the healthy-adherer effect.

These distinctions yield a reasonably clear clinical position. Patients most likely to benefit have a demonstrable allergen-driven mechanism, partially (not well) controlled asthma, preserved lung function and coexisting AR/C, with HDM sensitization being the best-supported phenotype. Benefit was not shown in patients already well controlled on ICS, and AIT is contraindicated in uncontrolled or unstable asthma. In children with AR/C, the decision is weighted more by the prospect of preventing onset within the early “window of opportunity” than by current symptoms.

Conclusion

AIT remains the only treatment for AA with demonstrated disease-modifying potential, offering benefit beyond symptom control. It is most firmly established for HDM-driven disease in adolescents/adults and for prevention of asthma onset in AR/C children, but still provisional for progression, decade-long durability, and severe asthma. It is thus best positioned as a targeted add-on therapy for the allergen-driven phenotype rather than a standalone asthma treatment. Converting these provisional findings into established ones will require adequately powered pediatric RCTs with standardized endpoints, randomized evaluation of progression, and prospective study of AIT combined with biologics.

Abbreviations

AA, allergic asthma; ACQ, Asthma Control Questionnaire; ACT, Asthma Control Test; AIT, allergen immunotherapy; AQLQ, Asthma Quality of Life Questionnaire; AR, allergic rhinitis; AR/C, allergic rhinitis with or without conjunctivitis; ASS, asthma symptom score; FEV₁, forced expiratory volume in the 1st second; GINA, Global Initiative for Asthma; HDM, house dust mite; HR, hazard ratio; ICS, inhaled corticosteroid; IgE, immunoglobulin E; IL, interleukin; IR, index of reactivity; LABA, long-acting β₂-agonist; OR, odds ratio; PAQLQ, Pediatric Asthma Quality of Life Questionnaire; QoL, quality of life; RCTs, randomized controlled trials; RDBPCT, randomized double-blind placebo-controlled trial; RR, relative risk; RSS, rhinitis symptom score; SABA, short-acting β₂-agonist; SCIT, subcutaneous immunotherapy; SLIT, sublingual immunotherapy; SMD, standardized mean difference; SQ, standardized quality; Th2, T helper 2; TSS, total symptom score; TU, therapeutic units; VAS, visual analogue scale.

Disclosure

FC reports personal fees from Hippo Dx. MG reports personal fees from Sanofi, Thermo Fisher Scientific. GP reports fees for speaker activities and/or advisory boards participation from Lofarma, GSK, Menarini, Firma, Sanofi and AstraZeneca, outside the submitted work. RC has been awarded institutional grants from Asthma+Lung UK, Chiesi, AstraZeneca, GSK and Sanofi-Regeneron; served on advisory boards for Vitalograph, Chiesi and AstraZeneca; received personal fees from AstraZeneca, Chiesi, Vitalograph, Thorasys, GSK, Jaeger and Sanofi-Regeneron; and support attending conferences from AstraZeneca, Chiesi, NIOX, Sanofi-Regeneron and Vitalograph GWC reports research or clinical trials grants paid to his Institution from Menarini, AstraZeneca, GSK, Sanofi Genzyme and fees for lectures or advisory board participation from Menarini, AstraZeneca, CellTrion, Chiesi, Faes Farma, Firma, Genentech, Guidotti-Malesci, GSK, HAL Allergy, Innovacaremd, Novartis, OM-Pharma, Red Maple, Sanofi-Aventis, Sanofi-Genzyme, Stallergenes-Greer and Uriach Pharma. EH reports fees for Advisory Boards participation and/or speaker’s fee from AstraZeneca, Sanofi, Regeneron, GSK, Celltrion Healthcare, Apogee Therapeutics, Chiesi,Almirall, Lofarma, Allergy Therapeutics, Firma, Gentili, Blueprint Medicines, Bosch Healthcare, Insmed, Recordati, Orion Pharma. GG reports fees for speaker activities from Menarini and Sanofi FLMR reports grants, personal fees, and other compensation from AstraZeneca, Chiesi, GSK, Zambon, and Sanofi-Regeneron all outside of the submitted work. The authors report no other conflicts of interest in this work.