Preventive effects of sublingual immunotherapy in childhood: an open randomized controlled study

doi:10.1016/S1081-1206(10)60211-6

Annals of Allergy, Asthma & Immunology

Volume 101, Issue 2, August 2008, Pages 206-211

https://doi.org/10.1016/S1081-1206(10)60211-6 Get rights and content

Background

Sublingual immunotherapy (SLIT) has been proved to be effective in allergic rhinitis and asthma, but there are few data on its preventive effects, especially in children.

Objective

To evaluate the clinical and preventive effects of SLIT in children by assessing onset of persistent asthma and new sensitizations, clinical symptoms, and bronchial hyperreactivity.

Methods

A total of 216 children with allergic rhinitis, with or without intermittent asthma, were evaluated and then randomized to receive drugs alone or drugs plus SLIT openly for 3 years. The clinical score was assessed yearly during allergen exposure. Pulmonary function testing, methacholine challenge, and skin prick testing were performed at the beginning and end of the study.

Results

One hundred forty-four children received SLIT and 72 received drugs only. Dropouts were 9.7% in the SLIT group and 8.3% in the controls. New sensitizations appeared in 34.8% of controls and in 3.1% of SLIT patients (odds ratio, 16.85; 95% confidence interval, 5.73-49.13). Mild persistent asthma was less frequent in SLIT patients (odds ratio, 0.04; 95% confidence interval, 0.01-0.17). There was a significant decrease in clinical scores in the SLIT group vs the control group since the first year. The number of children with a positive methacholine challenge result decreased significantly after 3 years only in the SLIT group. Adherence was 80% or higher in 73.8% of patients. Only 1 patient reported systemic itching.

Conclusions

In everyday clinical practice, SLIT reduced the onset of new sensitizations and mild persistent asthma and decreased bronchial hyperreactivity in children with respiratory allergy.

Section snippets

INTRODUCTION

Since its introduction in 1986,¹ sublingual immunotherapy (SLIT) has been a promising alternative to traditional subcutaneous immunotherapy (SCIT). During the past 20 years, numerous controlled trials and several meta-analyses2, 3, 4, 5 have confirmed its efficacy in respiratory allergy in adults and children. In addition, studies have demonstrated the satisfactory safety profile of SLIT and the low occurrence of adverse effects,6, 7, 8 even in children younger than 5 years9, 10 or with

General Plan

This study was designed to compare SLIT added to drug therapy with drug therapy alone in preventing the onset of (1) persistent asthma and (2) new sensitizations. Secondary objectives were to evaluate the magnitude of the clinical effect, the effect on bronchial hyperreactivity, the safety, and the adherence to SLIT. The study was designed to be open, controlled, and randomized. Pediatric outpatients fulfilling the inclusion criteria were evaluated during a baseline 1-year period and then were

RESULTS

Of 216 children (147 boys; mean age, 10 years) fulfilling the inclusion criteria and enrolled in this trial, 144 were allocated to receive SLIT in addition to drug therapy. All these children were prescribed SLIT for a single allergen, as follows: 98 for mites, 41 for grasses, 4 for birch, and 1 for Parietaria. During the 3-year randomized trial, 20 patients dropped out, but the dropout frequency did not differ in children undergoing SLIT (14 of 144) vs controls (6 of 72) (P = .76) (Fig 2).

DISCUSSION

Although the clinical efficacy of SLIT has been confirmed in several studies, concerns still exist about its preventive effects (eg, on new skin sensitizations and asthma onset). Indeed, the literature includes some positive results concerning the prevention of asthma onset,²² bronchial hyperresponsiveness,²⁹ and asthma worsening,³⁰ but these trials usually involved few patients, and the results could be questioned from a methodological point of view.³¹

In the present study, we aimed to assess

ACKNOWLEDGMENTS

We thank the patients and their parents for their availability in taking part in this trial and for the excellent cooperation they have shown.

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Allergen immunotherapy is highly effective for seasonal pollinosis. Three years of treatment results in long-term efficacy. This disease modification is accompanied by downregulation of allergen-specific Th2 responses and the induction of persistent specific IgG- and IgA-associated IgE-blocking activity. In children with seasonal rhinitis, both subcutaneous and sublingual pollen immunotherapy have been shown to reduce the development of asthma symptoms and asthma medication requirements. House dust mite tablet allergen immunotherapy has been shown to be effective for perennial mite–driven rhinitis in adults and children and may suppress asthma exacerbations, whereas its long-term efficacy has yet to be explored. The success of primary prevention of peanut allergy in childhood by introduction of peanut into the diet during infancy provides a strong rationale to explore whether primary prevention of inhalant allergies and asthma may also be possible. House dust mite allergy is a major risk factor for developing asthma. Preliminary data in at-risk children suggest that sublingual house dust mite immunotherapy initiated during infancy could reduce the onset of multiple allergen sensitizations and prevent the development of asthma at age 6 years. This possibility should now be explored in an adequately powered, prospectively randomized controlled trial.
Extrapolating Evidence-Based Medicine of AIT Into Clinical Practice in the United States
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Allergy/immunology specialists in the United States prescribing allergy immunotherapy (AIT) have placed a heavy value on practical experience and anecdotal evidence rather than research-based evidence. With the extensive research on AIT conducted in the last few decades, the time has come to better implement evidence-based medicine (EBM) for AIT. The goal of this review was to critically assess EBM for debated concepts in US AIT practice for respiratory allergies in the context and quality of today’s regulatory standards. Debated topics reviewed were the efficacy and safety of AIT in various subgroups (eg, polyallergic patients, older patients, patients with asthma, and pregnant women), diagnosis topics (eg, skin prick test vs allergen-specific serum IgE, factors affecting skin prick tests, use of nasal or conjunctival allergen challenges, and telemedicine for diagnosis), and dosing topics (eg, optimal dosing for subcutaneous immunotherapy and sublingual immunotherapy tablets, US liquid allergen extract history, duration of treatment, and biomarkers of efficacy). In addition, EBM for patient-centered AIT issues (eg, adherence, use of practice guidelines, and pharmacoeconomics) and the approach to implementation of AIT EBM in future clinical practice were addressed. The EBM for each concept was briefly summarized, and when possible, a practical, concise recommendation was given.
Does allergen immunotherapy for allergic rhinitis prevent asthma?
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Citation Excerpt :
SLIT not only improved hay fever symptoms, but there was a nearly 4-fold reduction in the development of asthma over this period. Subsequently, the preventive effect of SLIT on asthma and BHR in children was evaluated in a larger open RCT of 216 children (SLIT = 144; standard therapy = 72).24 After 3 years, SLIT-treated children had less mild persistent asthma (OR, 0.04; 95% CI, 0.01-0.17) and the number of children with a positive methacholine challenge result decreased after 3 years, only in the SLIT group.
Asthma and allergic rhinitis (AR) have overlapping clinical and pathologic features, sustained by an underlying T helper 2 bias, resulting in airway inflammation that extends from the nose to the lung. Children who are monosensitized often develop polysensitization over time, and they are at high risk of developing asthma. The effect of allergen immunotherapy (AIT) is allergen specific, resulting in symptom improvement and reduction in medication requirement. It is the only known treatment that alters the natural history of allergic disease and induces long-term remission. A bystander or allergen-nonspecific effect of AIT has also been proposed—that AIT to 1 allergen might reduce the risk of development of sensitization to other allergens. Furthermore, several observational studies and clinical trials, in seasonal (pollen) and perennial (house dust mite) AR, have investigated a protective effect of AIT to prevent asthma. The overall evidence favors an asthma preventive effect of AIT in AR to grass and birch tree pollen. Fewer studies have investigated the use of AIT in children with perennial AR due to house dust mite allergy to prevent asthma, and the results are less convincing. The use of AIT to reduce the risk of progression to asthma, in children with AR, potentially has high impact, and it will make AIT more attractive and cost-effective. However, most studies have been of small sample size or of poor design, using different allergens and AIT methodology, making it challenging to draw firm conclusions. There is a need to do adequately powered studies with optimal design and assess cost-effectiveness of this strategy.
Allergen immunotherapy for long-term tolerance and prevention
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Allergen immunotherapy is effective for the treatment of allergic rhinitis, allergic asthma, and Hymenoptera venom allergy. In view of potential side effects, cost, and the necessary patient commitment, an important question is whether allergen immunotherapy provides persistent clinical benefits after treatment discontinuation. Here, we appraise the existing evidence for long-term effects of both subcutaneous and sublingual immunotherapy in terms of clinical efficacy, immune mechanisms, prevention of asthma development, and prevention of new allergen sensitizations. Evidence from large, randomized, double-blind, placebo-controlled clinical trials that include a follow-up phase after treatment cessation demonstrate long-term efficacy. The data strongly support recommendations in international guidelines that both sublingual and subcutaneous immunotherapy should be continued for a minimum of 3 years to achieve disease modification and long-term tolerance. Grass pollen immunotherapy for seasonal rhinitis may inhibit the onset of asthma symptoms and requirements for asthma medication. Whether early intervention in infancy with mite sublingual immunotherapy may prevent asthma remains to be tested.
Allergic Rhinitis in Children and Adolescents
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Preventive Effect of Allergen Immunotherapy on Asthma and New Sensitizations
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Allergen immunotherapy (AIT) is a disease-modifying treatment for some IgE-mediated allergic diseases with the potential to have important preventive effects. Children with allergic rhinitis have a high risk of developing asthma, and treating allergic rhinitis with AIT may interfere with disease progression and prevent onset of asthma. Although the evidence is limited due to relatively few and heterogeneous studies, data nevertheless suggest that AIT has a preventive effect on development of asthma especially in children with rhinitis due to grass pollen allergy. AIT may also affect the development of new sensitizations. Both the degree of sensitization and the specific sensitization pattern may influence future disease severity and development of comorbidities. Hitherto, the indication for AIT for prevention of development of asthma in grass/birch pollen allergic children has been the same as for treatment of allergic rhinitis. Probably, AIT should be applied in the early stage of the allergic disease to have the greatest preventive effect on disease progression. Consequently, in the future, the potential preventive effects should influence the timing of initiating AIT. The window of opportunity to prevent asthma may primarily exist in young children with mild symptoms and a low degree of sensitization.

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: Disclosures: Authors have nothing to disclose.

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Original Articles: InterventionsPreventive effects of sublingual immunotherapy in childhood: an open randomized controlled study

Background

Objective

Methods

Results

Conclusions

Section snippets

INTRODUCTION

General Plan

RESULTS

DISCUSSION

ACKNOWLEDGMENTS

Ann Allergy Asthma Immunol

Chest

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Lancet

Low dose sublingual therapy in patients with allergic rhinitis due to house dust mite

Clin Allergy

Sublingual immunotherapy for allergic rhinitis

Cochrane Database Syst Rev.

Sublingual immunotherapy in asthma and rhinoconjunctivitis: systematic review of paediatric literature

Arch Dis Child

Post-marketing surveillance study on the safety of sublingual immunotherapy in children

Allergy

Safety of sublingual immunotherapy in adults: a post- marketing surveillance study

Allergy

Safety of sublingual immunotherapy in children with asthma

Paediatr Drugs

Post-marketing surveillance on the safety of sublingual immunotherapy in children below the age of 5 years

Clin Exp Allergy

Safety of SLIT in very young children

Allergy

Safety and tolerability of ultra-rush induction, less than one hour, of sublingual immunotherapy in children

Int Arch Allergy Immunol

Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study

Allergy

Effect of immunotherapy on asthma progression, BHR and sputum eosinophils in allergic rhinitis

Allergy

Original Articles: Interventions
Preventive effects of sublingual immunotherapy in childhood: an open randomized controlled study