Prevention Is Better than Cure: Impact of Allergen Immunotherapy on the Progression of Airway Disease.

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.

Nasal and blood transcriptomic pathways underpinning the clinical response to grass pollen immunotherapy.

BACKGROUND: Allergen immunotherapy (AIT) is a well-established disease-modifying therapy for allergic rhinitis, yet the fundamental mechanisms underlying its clinical effect remain inadequately understood. Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy was a randomized, double-blind, placebo-controlled trial of individuals allergic to timothy grass who received 2 years of placebo (n = 30), subcutaneous immunotherapy (SCIT) (n = 27), or sublingual immunotherapy (SLIT) (n = 27) and were then followed for 1 additional year. OBJECTIVE: We used yearly biospecimens from the Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy study to identify molecular mechanisms of response. METHODS: We used longitudinal transcriptomic profiling of nasal brush and PBMC samples after allergen provocation to uncover airway and systemic expression pathways mediating responsiveness to AIT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01335139, EudraCT Number: 2010-023536-16. RESULTS: SCIT and SLIT demonstrated similar changes in gene module expression over time. In nasal samples, alterations included downregulation of pathways of mucus hypersecretion, leukocyte migration/activation, and endoplasmic reticulum stress (log2 fold changes -0.133 to -0.640, false discovery rates [FDRs] <0.05). We observed upregulation of modules related to epithelial development, junction formation, and lipid metabolism (log2 fold changes 0.104 to 0.393, FDRs <0.05). In PBMCs, modules related to cellular stress response and type 2 cytokine signaling were reduced by immunotherapy (log2 fold changes -0.611 to -0.828, FDRs <0.05). Expression of these modules was also significantly associated with both Total Nasal Symptom Score and peak nasal inspiratory flow, indicating important links between treatment, module expression, and allergen response. CONCLUSIONS: Our results identify specific molecular responses of the nasal airway impacting barrier function, leukocyte migration activation, and mucus secretion that are affected by both SCIT and SLIT, offering potential targets to guide novel strategies for AIT.

Long-term efficacy of the sublingual and subcutaneous routes in allergen immunotherapy.

Allergen immunotherapy is highly effective in selected patients with allergic rhinitis, allergic asthma, and Hymenoptera venom allergy. Unlike anti-allergic drugs, both subcutaneous and sublingual immunotherapies have been shown to modify the underlying cause of the disease, with proved long-term clinical benefits after treatment cessation. In this review, we analyzed 10 randomized, double-blind, placebo controlled clinical trials of allergen immunotherapy that included blinded follow-up for at least 1 year after treatment withdrawal. Three studies of pollen subcutaneous immunotherapy provided evidence that a sustained, tolerogenic effect of subcutaneous immunotherapy can be achieved after 3 years of treatment. Six trials of sublingual immunotherapy provided robust evidence for long-term clinical benefit and persistent immunologic changes after grass pollen, house-dust mite, or Japanese cedar immunotherapy, whereas a clinical trial of both sublingual and subcutaneous grass pollen immunotherapies showed that 2 years of immunotherapy were efficacious but insufficient to induce long-term tolerance. These studies strongly supported international guidelines that recommend at least 3 years of allergen immunotherapy of proven value to achieve disease modification and sustained clinical and immunologic tolerance.

Allergen immunotherapy for long-term tolerance and prevention.

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.

Immunological Responses and Biomarkers for Allergen-Specific Immunotherapy Against Inhaled Allergens.

Long-term efficacy that occurs with allergen immunotherapy of proven value is associated with decreases in IgE-dependent activation of mast cells and tissue eosinophilia. This suppression of type 2 immunity is accompanied by early induction of regulatory T cells, immune deviation in favor of TH1 responses, and induction of local and systemic IgG, IgG4, and IgA antibodies. These "protective" antibodies can inhibit allergen-IgE complex formation and consequent mast cell triggering and IgE-facilitated TH2-cell activation. Recent studies have highlighted the importance of innate responses mediated by type 2 dendritic cells and innate lymphoid cells in allergic inflammation. These cell types are under the regulation of cytokines such as thymic stromal lymphopoietin and IL-33 derived from the respiratory epithelium. Novel subsets of regulatory cells induced by immunotherapy include IL-35-producing regulatory T cells, regulatory B cells, a subset of T follicular regulatory cells, and IL-10-producing group 2 innate lymphoid cells. These mechanisms point to biomarkers that require testing for their ability to predict clinical response to immunotherapy and to inform novel approaches for better efficacy, safety, and long-term tolerance.

Duration of allergen immunotherapy for inhalant allergy.

PURPOSE OF REVIEW: We evaluated the time-course of clinical and immunologic changes that occur during and after cessation of sublingual and subcutaneous allergen immunotherapy for inhalant allergies. RECENT FINDINGS: Increases in production of inhibitory cytokines, such as IL-10 and allergen-specific IgE and IgG4 antibodies are induced within weeks of starting immunotherapy for both seasonal and perennial allergens. In general, 2-4 months' immunotherapy is needed for onset of efficacy whereas maximal clinical effect is achieved within 1-2 years of treatment. Therefore, assuming optimal patient selection, good compliance and at least moderate allergen exposure, if immunotherapy is ineffective at 2 years, it is reasonable to discontinue the treatment. For long-term clinical efficacy, at least 3 years of either subcutaneous or sublingual immunotherapy is required and this results in clinical and immunologic tolerance -- persistence of clinical benefits and suppression of type 2 immunity for years after discontinuation of treatment. SUMMARY: Both sublingual and subcutaneous immunotherapy are effective and well tolerated for respiratory allergy. Clinical and immunological changes occur at early stages of treatment. Long-term evaluations support recommendations in international guidelines that both routes of administration should be continued for a minimum of 3 years to achieve disease modification and long-term tolerance.

Duration of Allergen Immunotherapy for Long-Term Efficacy in Allergic Rhinoconjunctivitis.

RATIONALE: Subcutaneous and sublingual immunotherapy are effective for allergic rhinitis. An important question is whether allergen immunotherapy provides a sustained clinical effect after treatment cessation. In view of potential side effects, cost and the necessary patient commitment, long-term benefit is an important consideration for the recommendation of immunotherapy over standard pharmacotherapy. PURPOSE OF REVIEW: In this review, we analyse the existing evidence for long-term effects of both routes of administration in the context of double-blind, placebo-controlled, randomised clinical trials that included a follow-up phase of at least 1 year after treatment cessation. RECENT FINDINGS: Overall, evidence suggests that 3 years of either subcutaneous or sublingual immunotherapy result in clinical benefit and immunological changes consistent with allergen-specific tolerance sustained for at least 2-3 years after treatment cessation. SUMMARY: The data presented here support recommendations in international guidelines that both routes of administration should be continued for a minimum of 3 years. Gaps in the evidence remain regarding the long-term efficacy of immunotherapy for perennial rhinitis and studies performed in children.

EAACI guidelines on allergen immunotherapy: Prevention of allergy.

Allergic diseases are common and frequently coexist. Allergen immunotherapy (AIT) is a disease-modifying treatment for IgE-mediated allergic disease with effects beyond cessation of AIT that may include important preventive effects. The European Academy of Allergy and Clinical Immunology (EAACI) has developed a clinical practice guideline to provide evidence-based recommendations for AIT for the prevention of (i) development of allergic comorbidities in those with established allergic diseases, (ii) development of first allergic condition, and (iii) allergic sensitization. This guideline has been developed using the Appraisal of Guidelines for Research & Evaluation (AGREE II) framework, which involved a multidisciplinary expert working group, a systematic review of the underpinning evidence, and external peer-review of draft recommendations. Our key recommendation is that a 3-year course of subcutaneous or sublingual AIT can be recommended for children and adolescents with moderate-to-severe allergic rhinitis (AR) triggered by grass/birch pollen allergy to prevent asthma for up to 2 years post-AIT in addition to its sustained effect on AR symptoms and medication. Some trial data even suggest a preventive effect on asthma symptoms and medication more than 2 years post-AIT. We need more evidence concerning AIT for prevention in individuals with AR triggered by house dust mites or other allergens and for the prevention of allergic sensitization, the first allergic disease, or for the prevention of allergic comorbidities in those with other allergic conditions. Evidence for the preventive potential of AIT as disease-modifying treatment exists but there is an urgent need for more high-quality clinical trials.

Effect of 2 Years of Treatment With Sublingual Grass Pollen Immunotherapy on Nasal Response to Allergen Challenge at 3 Years Among Patients With Moderate to Severe Seasonal Allergic Rhinitis: The GRASS Randomized Clinical Trial.

Importance: Sublingual immunotherapy and subcutaneous immunotherapy are effective in seasonal allergic rhinitis. Three years of continuous treatment with subcutaneous immunotherapy and sublingual immunotherapy has been shown to improve symptoms for at least 2 years following discontinuation of treatment. Objective: To assess whether 2 years of treatment with grass pollen sublingual immunotherapy, compared with placebo, provides improved nasal response to allergen challenge at 3-year follow-up. Design, Setting, and Participants: A randomized double-blind, placebo-controlled, 3-parallel-group study performed in a single academic center, Imperial College London, of adult patients with moderate to severe seasonal allergic rhinitis (interfering with usual daily activities or sleep). First enrollment was March 2011, last follow-up was February 2015. Interventions: Thirty-six participants received 2 years of sublingual immunotherapy (daily tablets containing 15 µg of major allergen Phleum p 5 and monthly placebo injections), 36 received subcutaneous immunotherapy (monthly injections containing 20 µg of Phleum p 5 and daily placebo tablets) and 34 received matched double-placebo. Nasal allergen challenge was performed before treatment, at 1 and 2 years of treatment, and at 3 years (1 year after treatment discontinuation). Main Outcomes and Measures: Total nasal symptom scores (TNSS; range; 0 [best] to 12 [worst]) were recorded between 0 and 10 hours after challenge. The minimum clinically important difference for change in TNSS within an individual is 1.08. The primary outcome was TNSS comparing sublingual immunotherapy vs placebo at year 3. Subcutaneous immunotherapy was included as a positive control. The study was not powered to compare sublingual immunotherapy with subcutaneous immunotherapy. Results: Among 106 randomized participants (mean age, 33.5 years; 34 women [32.1%]), 92 completed the study at 3 years. In the intent-to-treat population, mean TNSS score for the sublingual immunotherapy group was 6.36 (95% CI, 5.76 to 6.96) at pretreatment and 4.73 (95% CI, 3.97 to 5.48) at 3 years, and for the placebo group, the score was 6.06 (95% CI, 5.23 to 6.88) at pretreatment and 4.81 (95% CI, 3.97 to 5.65) at 3 years. The between-group difference (adjusted for baseline) was -0.18 (95% CI, -1.25 to 0.90; [P = .75]). Conclusions and Relevance: Among patients with moderate to severe seasonal allergic rhinitis, 2 years of sublingual grass pollen immunotherapy was not significantly different from placebo in improving the nasal response to allergen challenge at 3-year follow-up. Trial Registration: clinicaltrials.gov Identifier: NCT01335139; EudraCT Number: 2010-023536-16.

Allergen immunotherapy for the prevention of allergy: A systematic review and meta-analysis.

BACKGROUND: There is a need to establish the effectiveness, cost-effectiveness, and safety of allergen immunotherapy (AIT) for the prevention of allergic disease. METHODS: Two reviewers independently screened nine international biomedical databases. Studies were quantitatively synthesized using random-effects meta-analyses. RESULTS: A total of 32 studies satisfied the inclusion criteria. Overall, meta-analysis found no conclusive evidence that AIT reduced the risk of developing a first allergic disease over the short term (RR = 0.30; 95% CI: 0.04-2.09) and no randomized controlled evidence was found in relation to its longer-term effects for this outcome. There was, however, a reduction in the short-term risk of those with allergic rhinitis developing asthma (RR = 0.40; 95% CI: 0.30-0.54), with this finding being robust to a pre-specified sensitivity analysis. We found inconclusive evidence that this benefit was maintained over the longer term: RR = 0.62; 95% CI: 0.31-1.23. There was evidence that the risk of new sensitization was reduced over the short term, but this was not confirmed in the sensitivity analysis: RR = 0.72; 95% CI: 0.24-2.18. There was no clear evidence of any longer-term reduction in the risk of sensitization: RR = 0.47; 95% CI: 0.08-2.77. AIT appeared to have an acceptable side effect profile. CONCLUSIONS: AIT did not result in a statistically significant reduction in the risk of developing a first allergic disease. There was, however, evidence of a reduced short-term risk of developing asthma in those with allergic rhinitis, but it is unclear whether this benefit was maintained over the longer term. We are unable to comment on the cost-effectiveness of AIT.

Sublingual or subcutaneous immunotherapy for allergic rhinitis?

Allergen immunotherapy is effective in patients with allergic rhinitis (AR) and, unlike antiallergic drugs, has been shown to modify the underlying cause of the disease, with proved long-term benefits. Subcutaneous immunotherapy (SCIT) has been the gold standard, whereas sublingual immunotherapy (SLIT) has emerged as an effective and safe alternative. Previous Cochrane systematic reviews and meta-analyses have confirmed that both SLIT and SCIT are effective in patients with seasonal AR, whereas evidence for their efficacy in patients with perennial disease has been less convincing. Recent large, adequately powered trials have demonstrated reductions in both symptoms and use of rescue medication in patients with seasonal and those with perennial AR. Here we appraise evidence for SCIT versus SLIT based on indirect evidence from Cochrane reviews and recent well-powered double-blind, randomized controlled trials versus placebo and the limited direct evidence available from randomized blind head-to-head comparisons. At present, based on an overall balance of efficacy and side effects, the patient is in equipoise. Pending definitive comparative trials, choice might be determined largely by the local availability of SCIT and SLIT products of proved value and personal (patient) preference.

Protocol for a randomised, double-blind, placebo-controlled study of grass allergen immunotherapy tablet for seasonal allergic rhinitis: time course of nasal, cutaneous and immunological outcomes.

BACKGROUND: Seasonal Allergic Rhinitis is characterised by inflammation of the nasal mucosa upon exposure to common aeroallergens, affecting up to 20-25 % of the population. For those patients whose symptoms are not controlled by standard medical treatment, allergen specific immunotherapy is a therapeutic alternative. Although several studies have shown changes in immunologic responses as well as long term tolerance following treatment with a sublingual allergy immunotherapy tablet, a detailed time course of the early mechanistic changes of local and systemic T and B cell responses and the effects on B cell repertoire in the nasal mucosa have not been fully examined. METHODS/DESIGN: This is a randomized, double-blind, single-centre, placebo controlled, two arm time course study based in the United Kingdom comparing sublingual allergy immunotherapy tablet (GRAZAX(®), ALK-Abello Horsholm, Denmark) plus standard treatment with placebo plus standard treatment. Up to 50 moderate to severe grass pollen allergic participants will be enrolled to ensure randomisation of at least 44. Further, we shall enrol 20 non-atopic volunteers. Screening will be completed before eligible atopic participants are randomised to one of the two treatment arms in a 1 to 1 ratio. The primary endpoint will be the total nasal symptom score assessed over 60 min following grass pollen nasal allergen challenge after 12 months of treatment. Clinical assessments and/or mechanistic analyses on blood, nasal fluid, brushing and biopsies will be performed at baseline at 1, 2, 3, 4 (coinciding with the peak pollen season), 6 and 12 months of treatment. After 12 months of treatment, unblinding will take place. Those atopic participants receiving active treatment will continue therapy for another 12 months followed by a post treatment phase of 12 months. Assessments and collection of biologic samples from these participants will take place again at 24 and at 36 months from the start of treatment. The 20 healthy, non-atopic controls will undergo screening and one visit only coinciding with the 12 month visit for the atopic participants. DISCUSSION: The trial will end in April 2017. The trial is registered with ClinicalTrials.gov and the trial identifying number is NCT02005627. TRIAL REGISTRATION: Primary Registry: ClinicalTrials.gov, Trial Identifying number: NCT02005627, Secondary identifying numbers: EudraCT number: 2013-003732-72 REC: 13/EM/0351, Imperial College London (Sponsor): 13IC0847, Protocol Version 6.0, Date: 16.05.2014.

Peanut allergy: effect of environmental peanut exposure in children with filaggrin loss-of-function mutations.

BACKGROUND: Filaggrin (FLG) loss-of-function mutations lead to an impaired skin barrier associated with peanut allergy. Household peanut consumption is associated with peanut allergy, and peanut allergen in household dust correlates with household peanut consumption. OBJECTIVE: We sought to determine whether environmental peanut exposure increases the odds of peanut allergy and whether FLG mutations modulate these odds. METHODS: Exposure to peanut antigen in dust within the first year of life was measured in a population-based birth cohort. Peanut sensitization and peanut allergy (defined by using oral food challenges or component-resolved diagnostics [CRD]) were assessed at 8 and 11 years. Genotyping was performed for 6 FLG mutations. RESULTS: After adjustment for infantile atopic dermatitis and preceding egg skin prick test (SPT) sensitization, we found a strong and significant interaction between natural log (ln [loge]) peanut dust levels and FLG mutations on peanut sensitization and peanut allergy. Among children with FLG mutations, for each ln unit increase in the house dust peanut protein level, there was a more than 6-fold increased odds of peanut SPT sensitization, CRD sensitization, or both in children at ages 8 years, 11 years, or both and a greater than 3-fold increased odds of peanut allergy compared with odds seen in children with wild-type FLG. There was no significant effect of exposure in children without FLG mutations. In children carrying an FLG mutation, the threshold level for peanut SPT sensitization was 0.92 µg of peanut protein per gram (95% CI, 0.70-1.22 µg/g), that for CRD sensitization was 1.03 µg/g (95% CI, 0.90-1.82 µg/g), and that for peanut allergy was 1.17 µg/g (95% CI, 0.01-163.83 µg/g). CONCLUSION: Early-life environmental peanut exposure is associated with an increased risk of peanut sensitization and allergy in children who carry an FLG mutation. These data support the hypothesis that peanut allergy develops through transcutaneous sensitization in children with an impaired skin barrier.

Distribution of peanut protein in the home environment.

BACKGROUND: To halt the increase in peanut allergy, we must determine how children become sensitized to peanut. High household peanut consumption used as an indirect marker of environmental peanut exposure is associated with the development of peanut allergy. OBJECTIVE: We sought to validate a method to quantify environmental peanut exposure, to determine how peanut is transferred into the environment after peanut consumption, and to determine whether environmental peanut persists despite cleaning. METHODS: After initial comparative studies among 3 ELISA kits, we validated and used the Veratox polyclonal peanut ELISA to assess peanut protein concentrations in dust and air and on household surfaces, bedding, furnishings, hand wipes, and saliva. RESULTS: The Veratox polyclonal peanut ELISA had the best rate of recovery of an independent peanut standard. We demonstrated 100% sensitivity and specificity and a less than 15% coefficient of variation for intra-assay, interassay, and interoperator variability. There was high within-home correlation for peanut protein levels in dust and household surface wipes. Airborne peanut levels were lower than the limit of quantitation for the Veratox polyclonal peanut ELISA in a number of simulated scenarios, except for a brief period directly above peanuts being deshelled. Peanut protein persisted on hands and in saliva 3 hours after peanut consumption. Peanut protein was completely removed from granite tables after cleaning with detergent, and levels were reduced but still present after detergent cleaning of laminate and wooden table surfaces, pillows, and sofa covers. CONCLUSIONS: Peanut spread easily around the home and might be resistant to usual cleaning methods. Peanut protein can be transferred into the environment by means of hand transfer and saliva but is unlikely to be aerosolized.

Peanut protein in household dust is related to household peanut consumption and is biologically active.

BACKGROUND: Peanut allergy is an important public health concern. To understand the pathogenesis of peanut allergy, we need to determine the route by which children become sensitized. A dose-response between household peanut consumption (HPC; used as an indirect marker of environmental peanut exposure) and the development of peanut allergy has been observed; however, environmental peanut exposure was not directly quantified. OBJECTIVE: We sought to explore the relationship between reported HPC and peanut protein levels in an infant's home environment and to determine the biological activity of environmental peanut. METHODS: Peanut protein was quantified in wipe and dust samples collected from 45 homes with infants by using a polyclonal peanut ELISA. Environmental peanut protein levels were compared with peanut consumption assessed by using a validated peanut food frequency questionnaire and other clinical and household factors. Biological activity of peanut protein in dust was assessed with a basophil activation assay. RESULTS: There was a positive correlation between peanut protein levels in the infant's bed, crib rail, and play area and reported HPC over 1 and 6 months. On multivariate regression analysis, HPC was the most important variable associated with peanut protein levels in the infant's bed sheet and play area. Dust samples containing high peanut protein levels induced dose-dependent activation of basophils in children with peanut allergy. CONCLUSIONS: We have shown that an infant's environmental exposure to peanut is most likely to be due to HPC. Peanut protein in dust is biologically active and should be assessed as a route of possible early peanut sensitization in infants.

Early feeding practices and development of food allergies.

Despite increasing efforts to prevent food allergies in children, IgE-mediated food allergies continue to rise in westernized countries. Previous preventive strategies such as prolonged exclusive breastfeeding and delayed weaning onto solid foods have more recently been called into question. The present review discusses possible risk factors and theories for the development of food allergy. An alternative hypothesis is proposed, suggesting that early cutaneous exposure to food protein through a disrupted skin barrier leads to allergic sensitization and that early oral exposure of food allergen induces tolerance. Novel interventional strategies to prevent the development of food allergies are also discussed.

Sublingual immunotherapy for treating allergic conjunctivitis.

BACKGROUND: Allergic ocular symptoms, although frequently trivialised, are common and represent an important comorbidity of allergic rhinitis. Sublingual Immunotherapy (SLIT) is an effective and well-tolerated treatment for allergic rhinitis, but its effects on symptoms of ocular allergy have not been well established. OBJECTIVES: To evaluate the efficacy of SLIT compared with placebo for reductions in ocular symptoms, topical ocular medication requirements and conjunctival immediate allergen sensitivity. SEARCH STRATEGY: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2011, Issue 1), MEDLINE (January 1950 to January 2011), EMBASE (January 1980 to January 2011), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to January 2011), Web of Science (January 1970 to January 2011), Biosis Previews, (January 1979 to January 2011), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (January 2011), ClinicalTrials.gov (www.clinicaltrials.gov) (January 2011), the Australian New Zealand Clinical Trials Registry (ANZCTR) (www.actr.org.au) (July 2010), SCOPUS (November 2008) and the UK Clinical Trials Gateway (January 2010). There were no language or date restrictions in the search for trials. All electronic databases except for SCOPUS, the UK Clinical Trials Gateway and ANZCTR were last searched on 19 January 2011. SELECTION CRITERIA: Randomised controlled trials (RCTs), double-masked and placebo controlled, which evaluated the efficacy of SLIT in patients with symptoms of allergic rhinoconjunctivitis (ARC) or allergic conjunctivitis (AC). DATA COLLECTION AND ANALYSIS: The primary outcome was the total ocular symptom scores. Secondary endpoints included individual ocular symptom scores (such as itchy eyes, red eyes, watery eyes, swollen eyes), ocular medication scores (eye drops) and conjunctival immediate allergen sensitivity (CIAS). Data were analysed and reported as standardised mean differences (SMDs) using Review Manager software. MAIN RESULTS: Forty-two trials (n = 3958 total participants; n= 2011 SLIT and n = 1947 placebo) had available data to evaluate the efficacy of SLIT on AC and were included in the meta-analyses. Heterogeneity among studies (I(2) statistic) was around 50% or below for all endpoints. Sublingual immunotherapy induced a significant reduction in both total ocular symptom scores (SMD -0.41; 95% confidence interval (CI) -0.53 to -0.28; P < 0.00001; I(2) = 59%) and individual ocular symptom scores for red eyes (SMD -0.33; 95% CI -0.45 to -0.22; P < 0.00001; I(2) = 27%), itchy eyes (SMD -0.31; 95% CI -0.42 to -0.20; P < 0.00001; I(2) = 46%) and watery eyes (SMD -0.23; 95% CI -0.34 to -0.11; P < 0.0001; I(2) = 42%) compared to placebo. Those participants having active treatment showed an increase in the threshold dose for the conjunctival allergen provocation test (SMD 0.35; 95% CI 0.00 to 0.69; P = 0.05; I(2) = 43%). No significant reduction was observed in ocular eye drops use (SMD -0.10; 95% CI -0.22 to 0.03; P = 0.13; I(2) = 34%). AUTHORS' CONCLUSIONS: Overall, SLIT is moderately effective in reducing total and individual ocular symptom scores in participants with ARC and AC. There were however some concerns about the overall quality of the evidence-base, this relating to inadequate descriptions of allocation concealment in some studies, statistical heterogeneity and the possibility of publication bias. There is a need for further large rigorously designed studies that study long-term effectiveness after discontinuation of treatment and establish the cost-effectiveness of SLIT.

Immunotherapy: The meta-analyses. What have we Learned?

Meta-analysis is a powerful tool for evaluating the efficacy of a therapeutic intervention, and has clearly demonstrated that specific allergen immunotherapy (SIT) is effective for treating allergic rhinitis and asthma. Future research needs to focus on specifying the most effective forms of SIT for specific populations and allergens, using validated clinical outcomes, studying long-term outcomes (particularly the potential disease-modifying effect of immunotherapy), and assessing outcomes regarding health economics. The safety profile of SIT should be evaluated using international guidelines and terminology, and needs to include high-quality surveillance data.

The link between otitis media with effusion and allergy: a potential role for intranasal corticosteroids.

We reviewed the evidence linking otitis media with effusion (OME) and atopy, with the goal of clarifying the possible role of intranasal corticosteroids (INSs) in OME treatment. In August 2009, the MEDLINE database was searched for primary studies on OME epidemiology, pathophysiology, and treatment. Relevant clinical guidelines were obtained. Interpreting OME research is complicated by variable disease definitions, patient populations, methodologies, and outcomes assessments, along with the possibility of spontaneous resolution. However, evidence links OME with atopic conditions including allergic rhinitis; observed prevalence of allergic rhinitis in patients with chronic or recurrent OME ranges from 24% to 89%. Such findings have prompted evaluations of common allergy medications for OME treatment. While short-term use of INSs alone or combined with antibiotics has shown benefit in some studies, more prolonged treatment protocols and long-term clinical outcomes will require critical assessment. Evidence suggesting epidemiologic and pathophysiologic links between allergy and OME has prompted investigation into a potential role for INSs in OME management, with promising initial results. Benefits of considering medical treatment in patients with OME prior to surgery include both the potential reductions in allergic inflammation and the naturally occurring spontaneous resolution of OME in these patients.