Allergen immunotherapy in asthma.

Allergen immunotherapy (AIT), including SCIT and SLIT, is a treatment that involves the administration of allergens to which patients with allergic diseases have been sensitized. HDM-SCIT for asthma is indicated in cases of HDM-sensitized allergic asthma with normal lung function. HDM-SCIT improves asthma symptoms and AHR, and decreases the medication dose. Importantly, AIT can improve other allergic diseases complicated by asthma, such as allergic rhinitis, which can also contribute to the improvement of asthma symptoms. Several studies have suggested that HDM-SLIT also attenuates the risk of asthma exacerbations, and improves lung function in asthma cases with allergic rhinitis. Furthermore, AIT can modify the natural course of allergic diseases, including asthma. For example, the effects of AIT are maintained for at least several years after treatment discontinuation. AIT can prevent the onset of asthma when introduced in allergic rhinitis, and can also inhibit or reduce new allergen sensitizations. Recent data have suggested that AIT may suppress non-targeted allergen-induced immune responses in addition to targeted allergen-induced responses, and suppress infections of the lower respiratory tract by enhancing IFN responses.

Treatment with the SQ tree sublingual immunotherapy tablet is safe and well tolerated in real-life.

BACKGROUND: The SQ tree sublingual immunotherapy (SLIT)-tablet is authorised for treatment of allergic rhinoconjunctivitis with or without asthma in trees of the birch homologous group in 21 European countries. The primary objective of this study was to explore the safety in real-life. METHODS: In a prospective, non-interventional post-authorisation safety study (EUPAS31470), adverse events (AEs) and adverse drug reactions (ADRs) at first administration and follow-up visits, symptoms, medication use, and pollen food syndrome were recorded by physicians in 6 European countries during the first 4-6 months of treatment. RESULTS: ADRs with the SQ tree SLIT-tablet were reported in 57.7% of 1069 total patients (median age 36.0 years, 53.7% female) during the entire observation period (severity, mild-to-moderate: 70.1%, severe: 4.7%, serious: 0.7%) and in 45.9% after first administration. ADRs were not increased with pollen exposure at first administration. With coadministration of the SQ tree and grass SLIT-tablet AEs were reported in 73.8% of patients and in 52.8% with the SQ tree SLIT-tablet alone. Nasal and eye symptoms improved in 86.9% and 80.9% of patients and use of symptomatic medication in 76.0%. PFS with symptoms was reported in 43.0% of patients at baseline and in 4.3% at the individual last visit. CONCLUSIONS: The results of this non-interventional safety study with the SQ tree SLIT-tablet confirm the safety profile from placebo-controlled clinical trials and support effectiveness in real-life according to the published efficacy data. Safety was not impaired by pollen exposure at first administration or co-administration with other SLIT-tablets.

Transition between subcutaneous and sublingual allergen immunotherapy: Recommendations of the Brazilian Association of Allergy and Immunology (ASBAI).

The use of allergen immunotherapy (AIT) in Brazil has specific regional conditions owing to the pattern of allergen sensitization, as well as to genetic, socioeconomic, and cultural characteristics. This review article aims to discuss the clinical practice of AIT by the subcutaneous or sublingual route in Brazil, addressing the possibilities of transition between these forms of administration. A systematic review using the PubMed and Cochrane databases was performed, and the websites of major allergy and immunology organizations were consulted. Knowledge of the mechanism of action of subcutaneous immunotherapy and sublingual immunotherapy, together with Brazilian real-life experience, allowed us to establish recommendations regarding switching routes of AIT administration in selected cases. Careful analysis of each clinical situation is necessary to perform the transition between subcutaneous and sublingual allergen immunotherapy.

House dust mite immunotherapy: A real-world, prescription data-based analysis.

BACKGROUND: House dust mite (HDM) sensitisation can contribute to the development of allergic rhinoconjunctivitis (AR) or allergic asthma (AA). As treatment, allergen immunotherapy (AIT) is a promising approach, since it aims building immunotolerance against allergens, therewith establishing long-term efficacy. The evaluation of AIT has been investigated in many randomised controlled trials, whereas few real-world evidence studies are available. METHODS: We used data from the longitudinal prescription data base IQVIA™ LRx. Data on initial AIT prescriptions against HDM from January 2009 to December 2013 was analysed regarding treatment (subcutaneous AIT with either depigmented polymerised allergen extract [dSCIT] or other allergens [oSCIT], or sublingual immunotherapy [SLIT]) and treatment duration. Treatment groups were compared with a control group of AR patients not receiving AIT. Data on symptomatic medication was collected until February 2017 and progression of AR and AA was compared. RESULTS: Data of 7260 patients with AIT prescriptions and of 21,780 control patients was analysed. AIT was associated with a significant decrease of AR medication intake compared with control (dSCIT: -34.0%, p < 0.0001; oSCIT: -25.7%, p < 0.0001; SLIT: -37.7%, p = 0.0026). In asthmatics, SCIT was associated with a significant decrease of asthma medication compared with control (dSCIT: -45.2%, p < 0.0001; oSCIT: -32.9%, p < 0.0001). Further, a significantly reduced likelihood for onset of asthma medication was demonstrated in patients treated with SCIT compared with controls (dSCIT OR: 0.759, p = 0.0476; oSCIT OR: 0.815, p = 0.0339). CONCLUSION: Real-world data analyses indicate that AIT, particularly given via a subcutaneous route, reduces the need of medication against AR and AA and might delay the onset of asthma medication in patients with AR.

Fluctuation of Disease Severity and Quality of Life Applying Intralymphatic Immunotherapy for Patients with Seasonal Allergic Rhinitis.

Allergen-specific immunotherapy is the only disease-modifying treatment for IgE-mediated allergic disorders. Intra lymphatic immunotherapy (ILIT) is an efficacious and time-saving alternative to subcutaneous immunotherapy (SCIT). This study aimed to evaluate the effects and safety of ILIT in patients with moderate to severe allergic rhinitis.  In this clinical trial, patients between 18 and 65 years old with moderate to severe allergic rhinitis were enrolled. They received monthly intra-lymphatic inguinal injections of an active allergen (1000 SQ-U Salsola kali pollen). Their clinical symptoms were assessed before and four weeks after treatments. The clinical signs were also evaluated during two consecutive pollination seasons and the following non-pollination season in April. No moderate or severe reactions were recorded following ILIT treatment. Lymph node enlargement, angioedema/urticaria, and local itching were seen instantly after injection. Patients who received ILIT experienced a significant clinical improvement in self-recorded seasonal allergic symptoms after the treatments, compared to themselves before ILIT. Furthermore, their quality of life significantly improved. This study suggests ILIT with Salsola-pollen extract may decrease symptoms of allergic rhinitis. It was safe and did not cause any crucial complications.

Alternaria Allergy and Immunotherapy.

BACKGROUND: Allergen immunotherapy (AIT) is the only known causative treatment for Alternaria allergy, but the difficulty in standardizing Alternaria extracts hampers its effectiveness and safety. SUMMARY: Alternaria, a potent airborne allergen, has a high sensitization rate and is known to trigger the onset and exacerbation of respiratory allergies, even inducing fungal food allergy syndrome in some cases. It can trigger a type 2 inflammatory response, leading to an increase in the secretion of type 2 inflammatory cytokines and eosinophils, which are the culprits behind allergic symptoms. Diagnosing Alternaria allergy is a multistep process, involving a careful examination of clinical symptoms, medical history, skin prick tests, serum-specific IgE detection, or provocation tests. Alt a1, the major component of Alternaria, is a vital player in diagnosing Alternaria allergy through component-resolved diagnosis. Interestingly, Alternaria can reduce the protein activity of other allergens like pollen and cat dander when mixed with them. In order to solve the problems of standardization, efficacy and safety of traditional Alternaria AIT, novel AIT methods targeting Alt a1 and innovative vaccines such as epitope, DNA, and mRNA vaccines seem promising in bypassing the standardization issue of Alternaria extracts. But these studies are in early stages, and most researches are still focused on animal models, calling for more evidence to validate their use in humans. KEY MESSAGES: This review delves into the various aspects of Alternaria allergy, including characteristics, epidemiology, immune mechanisms, diagnosis, clinical manifestations, and the application and limitations of Alternaria AIT, aiming to provide a foundation for the management of patients with Alternaria allergy.

Elevated level of multibranched complex glycan reveals an allergic tolerance status.

BACKGROUND: Allergen immunotherapy (AIT) is the only disease-modifying therapy that can achieve immune tolerance in patients through long-term allergen stimulation. Glycans play crucial roles in allergic disease, but no information on changes in glycosylation related to an allergic tolerance status has been reported. METHODS: Fifty-seven patients with house dust mite (HDM) allergies were enrolled. Twenty-eight patients were not treated with AIT, 19 patients had just entered the AIT maintenance treatment phase, and 10 patients had been in the AIT maintenance phase for more than 1 year. Serum protein N-glycans were analyzed by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), which included linkage-specific sialylation information. RESULTS: Eighty-four N-glycans were identified in all three groups. Compared with the patients treated without AIT, the patients treated with AIT for a shorter time showed downregulated expression of high-mannose glycans and upregulated expression of α2,6 sialic acid. The patients treated with AIT in the maintenance phase for over 1 year, which was considered the start of immunological tolerance, showed downregulated expression of biantennary N-glycans and upregulated expression of multibranched and complex N-glycans. Nine N-glycans were changed between allergic and allergic-tolerant patients. CONCLUSIONS: The glycan form changed from mannose to a more complex type as treatment time increased, and multibranched complex glycans have the potential to be used as a monitoring indicator of immune tolerance. This serum N-glycome analysis provided important information for a deeper understanding of AIT treatment at the molecular level.

[Preventive effects of allergen immunotherapy to pneumallergens]. / Prévention des manifestations allergiques par une immunothérapie aux pneumallergènes.

Allergen immunotherapy is still the only curative treatment for respiratory allergies. It is based on repeated administration of allergenic extracts to sensitized patients. It can be administered either by subcutaneous or by sublingual route. The purpose of the treatment is to modulate the immune response to a specific allergen and to alter the course of the disease over a long-term period. Numerous studies and meta-analyses have demonstrated its efficacy in terms of symptoms and quality of life improvement as well as reduction of the allergic march. Indication of allergen immunotherapy includes moderate to severe allergic rhinitis and mild to moderate allergic asthma from GINA step 3. Early intervention in sensitized patients is nowadays promoted.

L'immunothérapie allergénique représente, encore aujourd'hui, le seul traitement curatif des allergies respiratoires. Elle consiste en l'administration répétée d'extraits allergéniques auxquels le patient est allergique. Elle peut se faire par voie sous-cutanée ou sublinguale. L'objectif est de moduler la réponse immunitaire afin de réduire les symptômes de l'allergie et de modifier le cours de la maladie allergique avec des effets perdurant sur le long terme. De nombreuses études et méta-analyses ont prouvé son efficacité en termes d'amélioration symptomatique, d'amélioration de la qualité de vie mais également de la réduction de l'évolution de la marche allergique. L'immunothérapie allergénique est indiquée dans le traitement de la rhinite allergique modérée à sévère et de l'asthme allergique dès le palier 3 du GINA («Global Initiative for Asthma¼). Une utilisation plus précoce est de plus en plus mise en avant pour bénéficier des effets préventifs de la modulation immunitaire.

Current Management of Allergic Rhinitis.

Allergic rhinitis (AR) is the most common allergic disease worldwide and one of the most common chronic diseases in general. Allergic rhinitis is caused by inhalant allergens from outdoor and indoor environments with varying significance of different allergens in global regions. We provide options for the current management for AR including pharmacological treatments and nonpharmacological options and allergen immunotherapy (AIT). A literature review has been conducted in Medline, Pubmed, as well as the national and international study (ClinicalTrials.gov) and guideline registers and the Cochrane Library. Human studies published on the topic in the period up to and including November 2023 were taken into account. Allergen avoidance measures, pharmacotherapy, and AIT are the cornerstones of AR treatment. Nonpharmacological measures and behavioral recommendations should be adequately added. Tools of precision medicine are already playing a significant role and will be part of the diagnostic and therapeutic standard in the future. Patients benefit most in a network of different pharmacological and nonpharmacological treatment measures including AIT. Application of precision medicine tools for diagnosis and treatment will improve standards of care.

Digitally-enabled, person-centred care (PCC) in allergen immunotherapy: An ARIA-EAACI Position Paper.

In rhinitis and asthma, several mHealth apps have been developed but only a few have been validated. However, these apps have a high potential for improving person-centred care (PCC), especially in allergen immunotherapy (AIT). They can provide support in AIT initiation by selecting the appropriate patient and allergen shared decision-making. They can also help in (i) the evaluation of (early) efficacy, (ii) early and late stopping rules and (iii) the evaluation of (carried-over) efficacy after cessation of the treatment course. Future perspectives have been formulated in the first report of a joint task force (TF)-Allergic Rhinitis and Its Impact on Asthma (ARIA) and the European Academy of Allergy and Clinical Immunology (EAACI)-on digital biomarkers. The TF on AIT now aims to (i) outline the potential of the clinical applications of mHealth solutions, (ii) express their current limitations, (iii) make proposals regarding further developments for both clinical practice and scientific purpose and (iv) suggest which of the tools might best comply with the purpose of digitally-enabled PCC in AIT.

How to hit the allergy target: A critical appraisal of intralymphatic immunotherapy with practical recommendations on ultrasound-guided injections.

BACKGROUND: Intralymphatic immunotherapy (ILIT) represents a promising novel approach treating allergic diseases. However, no standardized procedures or recommendations have been established or reported, despite the recognized fact that treatment efficacy relies on the ability to inject the allergen intranodally. OBJECTIVE: We aim to provide a critical appraisal of ILIT as a method of allergen immunotherapy and to deliver practical recommendations for accurate ILIT. METHODS: One hundred and seventy-three ILIT injections were performed in 28 (47%) women and 32 (53%) men with median age of 29 years (21-59). The injections were ultrasound-guided and recorded for retrospective analysis with respect to injection location, needle visibility, medication release, and patient characteristics. RESULTS: The results show that the correct positioning of the needle within the lymph node (LN) was most critical. If the whole length of the needle bevel was not inserted into the LN, substance backflush into the interstitium was observed. Selecting a more superficial LN and inserting the needle at a smaller angle towards the LN significantly improved needle visibility in the ultrasound. Longitudinal results showed that continuous practice significantly correlated with improved needle visibility and more accurate ILIT injections. CONCLUSION: Based on our results and practical experience, we propose several recommendations for LN selection and the correct handling of ultrasound probe and needle. We are confident that ILIT standardization and training will be important as to meet the goals of good safety and efficacy of ILIT.

Utility of silver birch and house dust mite extracts derived from licensed sublingual tablets for nasal allergen challenge.

BACKGROUND: Nasal allergen challenge (NAC) is used to investigate the effects of allergen exposure and assess treatment efficacy in allergic rhinitis (AR). This study aims to establish dose-responses to NAC using licensed silver birch (SB) pollen and house dust mite (HDM) sublingual tablets as sources of the allergen extracts in participants with AR. METHODS: Sixteen volunteers with HDM-induced perennial AR and 15 volunteers with SB pollen-induced seasonal rhinitis underwent a graded up-dosing NAC with extracts derived from HDM allergen (Acarizax®) and SB (Itulazax®) tablets, respectively. Total nasal symptom score (TNSS, range 0-12) and peak nasal inspiratory flow (PNIF) were recorded before, at 10 min and at the end of the NAC. The dose of each allergen that provoked a TNSS of at least 7 ("provoking dose 7") in most allergic participants was identified. NACs using the "provoking dose 7" were performed on 5 non-allergic individuals to test for irritant effects. The "provoking dose 7" of HDM extract was used in a subgroup of two SB allergic, non-HDM allergic, volunteers, and vice versa for SB extract, to test for allergen specificity of the responses. RESULTS: Most patients experienced a TNSS of at least 7/12 at a median concentration of 1500 AU/mL for both SB pollen and HDM. The average decline in PNIF at this dose was 63.15% for SB and 63.99% for HDM. NACs using the 1500 AU/mL concentrations were performed on 5 non-allergic individuals with no symptomatic or PNIF response. 1500 AU/mL of HDM extract produced no symptoms in SB allergics nor 1500 AU/mL SB extract in HDM allergics. CONCLUSION: For both SB and HDM extracts, the optimal allergen dose for NAC to cause a moderate-severity response ("provoking dose 7/12") was 1500 AU/mL. Licensed sublingual allergen tablets provide a readily available and inexpensive source of SB and HDM extracts for use in future interventional studies in AR.

A pediatric randomized, controlled trial of German cockroach subcutaneous immunotherapy.

BACKGROUND: Cockroach allergy contributes to morbidity among urban children with asthma. Few trials address the effect of subcutaneous immunotherapy (SCIT) with cockroach allergen among these at-risk children. OBJECTIVES: We sought to determine whether nasal allergen challenge (NAC) responses to cockroach allergen would improve following 1 year of SCIT. METHODS: Urban children with asthma, who were cockroach-sensitized and reactive on NAC, participated in a year-long randomized double-blind placebo-controlled SCIT trial using German cockroach extract. The primary endpoint was the change in mean Total Nasal Symptom Score (TNSS) during NAC after 12 months of SCIT. Changes in nasal transcriptomic responses during NAC, skin prick test wheal size, serum allergen-specific antibody production, and T-cell responses to cockroach allergen were assessed. RESULTS: Changes in mean NAC TNSS did not differ between SCIT-assigned (n = 28) versus placebo-assigned (n = 29) participants (P = .63). Nasal transcriptomic responses correlated with TNSS, but a treatment effect was not observed. Cockroach serum-specific IgE decreased to a similar extent in both groups, while decreased cockroach skin prick test wheal size was greater among SCIT participants (P = .04). A 200-fold increase in cockroach serum-specific IgG4 was observed among subjects receiving SCIT (P < .001) but was unchanged in the placebo group. T-cell IL-4 responses following cockroach allergen stimulation decreased to a greater extent among SCIT versus placebo (P = .002), while no effect was observed for IL-10 or IFN-γ. CONCLUSIONS: A year of SCIT failed to alter NAC TNSS and nasal transcriptome responses to cockroach allergen challenge despite systemic effects on allergen-specific skin tests, induction of serum-specific IgG4 serum production and down-modulation of allergen-stimulated T-cell responses.

Tablet allergen immunotherapy: the anaphylaxis issue.

For the first time 15 years ago, tablet allergen immunotherapy (T-AIT) formulations were approved by regulatory agencies for treating allergic rhinitis caused by grass pollen in adults and children aged >5 years. Extensive evidences existed about effectiveness and safety of AIT. However, the safety profile is particularly compelling in children. Generally, T-AIT causes local reactions, mostly in the oral cavity, that are usually mild-to-moderate and often self-resolving. However, systemic allergic reactions are also observed with T-AIT, anaphylaxis representing the most fearsome adverse event, considering that it occurs in subjects treated for allergic rhinitis. Therefore, we conducted a literature search of patients reporting anaphylaxis because of T-AIT. Nine cases of anaphylactic reactions were reported in literature. Notably, no death was reported using T-AIT. This outcome was very important as it underscored the substantial safety of T-AIT. However, T-AIT deserves careful attention, mainly in the pediatric population. In this regard, after the first report of anaphylactic reaction at the first administration of T-AIT, manufacturers recommended that the first dose should be administered in a medical facility in the presence of staff with experience in managing anaphylaxis and the patient should be observed for at least 30 min. Interestingly, reported anaphylactic reactions were due to grass pollen extracts, with no report concerning other allergen extracts. However, it is relevant to note that anaphylactic reactions because of T-AIT are not reported in recent years.

Preventive allergen immunotherapy with inhalant allergens in children.

The efficacy and safety of preventive allergen immunotherapy (pAIT) in children are currently under investigation. Here, we provide an overview of pAIT with respiratory allergens concerning the prevention of new sensitizations, allergic disease onset and progression as well as further immunomodulatory effects. Three databases were searched for clinical pAIT studies in children. Selected publications were reviewed for preventive outcomes according to prevention level (primary, secondary, and tertiary), allergen type, administration route, dose, and treatment duration. The primary prevention approach appears safe but showed no allergen-specific effect on new sensitizations. Secondary prevention seems feasible and may induce regulatory T cell-mediated immunotolerance. The number of studies at these prevention levels is limited. Tertiary prevention with grass and/or tree pollen-based pAIT has shown efficacy in preventing disease progression from allergic rhinitis/conjunctivitis to asthma. Data on tertiary pAIT with house dust mites and other allergen types are inconclusive. Subcutaneous and sublingual routes appear similarly effective, but head-to-head comparative paediatric studies are scarce. Additionally, there are fewer placebo-controlled studies. Nevertheless, immunomodulatory outcomes of pAIT are encouraging. Currently, limited but favourably suggestive evidence is available for preventing respiratory allergic diseases in children by pAIT. Primary and secondary prevention have potential and warrant further investigation through well-designed studies.

Current state and advances in desensitization for peanut allergy in pediatric age.

Peanut allergy affects about 1%-3% of the pediatric population in the world, with an important increase in the last decades. Nowadays, international guidelines recommend the early introduction of peanuts in the infant diet, with poor information about the quantity and the frequency of the intake. Allergen immunotherapy may represent the only therapeutic strategy able to modify the natural history of peanut allergy. In particular, oral immunotherapy showed the most promising results in terms of efficacy, but with significant rates of adverse reactions, mostly gastrointestinal. In 2020, the Food and Drug Administration and the European Medicines Agency approved Palforzia®, an oral drug for patients aged 4-17 years. Several studies are ongoing to improve the tolerability of oral immunotherapy and standardize the desensitization protocols. Sublingual immunotherapy permits to offer much lower doses than oral immunotherapy, but fewer adverse events are shown. Subcutaneous immunotherapy is associated with the greatest systemic adverse effects. Epicutaneous immunotherapy, for which Viaskin® patch was approved, has the highest safety profile. Innovative studies are evaluating the use of biological drugs, such as omalizumab or dupilumab, and probiotics, such as Lactobacillus rhamnosus, in monotherapy or associated with oral immunotherapy. Therapy for peanut allergy is constantly evolving, and new perspectives are ongoing to develop.

Respiratory allergic diseases and allergen immunotherapy: A French patient survey before and during the COVID-19 pandemic.

Background: The COVID-19 pandemic brought unprecedented global disruption to both healthcare providers and patients with respiratory allergies. There are limited real-life data on the impact of the COVID-19 pandemic on the risk perception of patients with allergy treated with allergen immunotherapy (AIT). Objective: To understand the risk perception of allergic patients treated with sublingual immunotherapy (SLIT) before and during the pandemic, and their attitudes towards COVID-19 infection and vaccination. Methods: This was a non-interventional, cross-sectional survey conducted from October to November 2021 in France. Adult patients, who had been prescribed and had received a Stallergenes SLIT (liquid or liquid and tablets) before the pandemic (from August 1, 2018 to March 10, 2020) and during the pandemic (from March 11, 2020 to August 31, 2021), were identified from the Stallergenes named-patient products (NPP) database. Patients completed an online questionnaire. Data were analyzed descriptively. Results: A total of 5258 patients from all over France completed the questionnaire. Mean (±SD) age of the respondents was 39.3 (±13.0) years and 66.9% were female. Some of them (11.8%) were obese (BMI >30 kg/m2). Main allergic diseases were rhinitis (80.0% of patients) with or without conjunctivitis, and asthma (39.0%). More than half of the patients experienced moderate to severe (58.0%) and persistent allergic rhinitis profile (70.4%). Most patients were poly-allergic (72.7%), mostly to house dust mites (61.9%), grass pollens (61.5%), tree pollens (57.8%), and cat dander (37.2%). Only 14.1% of patients experienced an aggravation of their allergy symptoms during lockdown and 14.8% were infected with COVID-19, with hospitalization required for 1.8%. Only 3.1% of patients reported their SLIT initiation as being postponed due to the pandemic. SLIT was changed, temporarily interrupted or permanently discontinued during the pandemic in 21.9% of patients. Changes mainly concerned the maintenance dose for SLIT-liquid (63.2%). SLIT modification was due to COVID-19 infection in only 4.2%. Most patients did not feel vulnerable (53.1%), anxious (55.2%), at risk to present severe symptoms of COVID-19 (77.1%), or at risk to transmit coronavirus (80.4%). However, greater anxiety was reported in patients with allergic asthma (33.6%) or other respiratory disorders (50.4%). Patients who felt vulnerable partly assigned their vulnerability to their allergic disease (59.3%). Suffering from an allergic disease did not make patients feel more vulnerable to side effects of COVID-19 vaccine for 79.6% of them. Conclusion: Overall, most patients with allergy and under SLIT were not strongly concerned by the COVID-19 infection. SLIT did not have a negative impact on the COVID-19 symptoms.