Subcutaneous Immunotherapy Research Articles

Efficacy of epinephrine rinse in allergen immunotherapy with aeroallergen and venom

Introduction In a suburban allergy outpatient office, the practice of epinephrine rinse of subcutaneous allergen immunotherapy (SCIT) syringes prior to injection has been employed for over 30 years with documented favorable clinical outcomes. A retrospective study was conducted to explore the effectiveness of epinephrine rinsing of SCIT syringes in managing local site reactions (LSR) in patients with allergen hypersensitivity. Methods Chart review of patients currently receiving SCITs was conducted using the clinical database at the outpatient office. 549 SCITs were reviewed, and 140 cases were traced to employ the use of epinephrine rinse to improve LSRs. The data was separated into allergic rhinitis and venom immunotherapy groups and was recorded for both build-up and maintenance phases. Results Out of 140 total patients requiring epinephrine rinse, 88.6% were in the allergic rhinitis group and 11.4% were in the venom group. In the allergic rhinitis group, 69.3% of patients and 87.5% in the venom group required epinephrine rinse during the build-up phase. In the allergic rhinitis group, 65.7% patients receiving SCIT at maintenance dose and 69.8% patients at build-up dose had resolution of LSR post-epinephrine rinse. In the venom group, 64.2% patients receiving SCITs at build-up dose improved LSR after epinephrine rinse. Conclusion Epinephrine rinse technique prior to injection showed favorable outcomes in over 60% of patients currently receiving treatment for allergen hypersensitivity. Epinephrine rinse is beneficial during the build-up phase of SCIT to manage LSR to effectively increase allergen dose.

Dose Adjustment After Gaps in Administration of Subcutaneous Immunotherapy From a Past Survey: Work Group Report of the AAAAI Allergen Standardization and Allergy Diagnostics Committee

The allergen immunotherapy practice parameters third update recommendations on dose adjustment after a gap in administration during the build-up are based solely on expert opinion, and no recommendations for gaps during maintenance are given. In a previous survey among American Academy of Allergy, Asthma & Immunology (AAAAI) members on subcutaneous allergen immunotherapy, this was addressed, but details were never published. Members of the Immunotherapy, Allergen Standardization, and Allergy Diagnostics Committee of the AAAAI convened a workgroup to address this issue and reanalyze results on the particular survey section. Build-up: many practitioners start dose-adjusting if a patient comes in 14.1/14 days (mean/median) after the last dose and restart immunotherapy after an interruption of 85/90 days. Dosing frequency during maintenance is generally every 3 (12%) to 4 weeks (73%). Maintenance: allergists start dose-adjusting if a patient comes in 5.1/5 weeks (mean/median) after the last dose and completely restart after an interruption of 16/12 weeks (some replied in days [90.4/90 days] or months [4.43/4 months]). Subgroups: physicians with ≥11 years in practice in nonacademic centers or rural/suburban settings tolerate longer gaps before restarting subcutaneous immunotherapy (SCIT). There is no uniform dose-adjustment protocol after gaps in SCIT administration. Prospective studies shall have to help find the best trade-off between safety (dose reduction) without giving in on efficacy (too much dose reduction).

Extracellular Vesicles Derived from Allergen Immunotherapy-Treated Mice Suppressed IL-5 Production from Group 2 Innate Lymphoid Cells.

Allergen immunotherapy (AIT), such as subcutaneous immunotherapy (SCIT), is a treatment targeting the causes of allergic diseases. The roles of extracellular vesicles (EVs), bilayer lipid membrane blebs released from all types of cells, in AIT have not been clarified. To examine the roles of EVs in SCIT, it was analyzed whether (1) EVs are phenotypically changed by treatment with SCIT, and (2) EVs derived from SCIT treatment suppress the function of group 2 innate lymphoid cells (ILC2s), which are major cells contributing to type 2 allergic inflammation. As a result, (1) expression of CD9, a canonical EV marker, was highly up-regulated by SCIT in a murine model of asthma; and (2) IL-5 production from ILC2s in vitro was significantly decreased by the addition of serum EVs derived from SCIT-treated but not non-SCIT-treated mice. In conclusion, it was indicated that EVs were transformed by SCIT, changing to a suppressive phenotype of type 2 allergic inflammation.

Effectiveness and adverse reactions to subcutaneous immunotherapy in children with allergic rhinitis/asthma.

Adverse reactions, which are mostly local and rarely systemic, can be seen during subcutaneous immunotherapy (SCIT). It was not possible to continue SCIT at times due to systemic reactions. The purpose of the present study was to identify the incidence and risk factors associated with adverse reactions during subcutaneous allergen-specific immunotherapy (AIT). A total number of 344 patients under 18 years old with allergic rhinitis and/or asthma who underwent SCIT between 2005 and 2021 were included in the study. Demographic characteristics of the patients, laboratory findings [Total Immunglobulin E(IgE), aeroallergen prick test, inhaler, and allergen specific IgE(sIgE) and eosinophil counts], and adverse events observed during AIT were recorded retrospectively. Descriptive and univariate/multivariate logistic regression analyses were used to identify risk factors for adverse events. Among 344 patients, 33.4% (n=115) were female, mean age was 133.1±41.0 months, and 42.2% (n=145) were >12 years old. One hundred-thirty eight (40.1%) of the patients were mono-sensitized, 47 (13.7%) had asthma, 207 (60.2%) allergic rhinitis, and 90 (26.2%) asthma and allergic rhinitis. Single allergen content was administered to 187 (54.4%) patients (62 mite, 114 grass mix, 11 olea), and multiple allergens to 157 (45.6%) patients (121 pollen mix, 36 other (mite/alternaria)]. A total number of 33.008 injections were administered. 840 adverse reactions (262 (31.1%) at up-dosing phase, 578 (68.8%) at maintenance phase) in 195 (56.7%) patients were observed. Among the adverse reactions, 632 (75.2%) were local, 160 (19%) large local, and 48 (5.7%) (39at maintenance, 9at up-dosing) (in 31 patients) were systemic (28 Grade 1, 12 Grade 2, 8 Grade 3). Adrenalin was administered to 8 patients with Grade 3 systemic reaction (8/33008; %0.024). Adverse reactions, especially local ones, were seen more frequently in children under 12 years old (p<0.001). Patients sensitized with grass pollen (p:0.01) and mite (p:0.004), and those who had received SCIT with pollen mixture had more adverse reactions than the others. More adverse reactions were observed in SCIT containing calcium-phosphate as adjuvant (p: 0.01). Local reactions were risk factors for large local (OR=3.591, %95 CI:2.064-6.247, p<0.001) and systemic (OR=2.190, %95 CI:1.005-4.722 p=0.046) reactions at univariate analyses. Total nasal symptom scores, Visual Analog Scale and asthma symptom control test decreased after one year of treatment (p<0.01). SCIT is a safe and effective treatment method in childhood that leads to improvements in all nasal symptoms and asthma after one year of treatment.

Effect of baseline serum vitamin D level on symptom and medication scores of subcutaneous immunotherapy in children with mite allergy.

Allergen immunotherapy (AIT) is considered to be the only treatment that may change the natural process of allergic diseases. Subcutaneous immunotherapy (SCIT) is a type of allergen immunotherapy that is commonly used in clinical practice. However, SCIT has inconsistent effects on individuals, and it is yet unclear what factors affect therapeutic efficacy. In recent years, vitamin D levels have been speculated as a potential factor influencing SCIT efficacy. To investigate the effect of serum vitamin D level on the SCIT efficacy in children with allergic rhinitis and/or asthma caused by dust mite allergy. According to the panel consensus, children with asthma and/or allergic rhinitis who received SCIT were divided into the vitamin D deficiency group (<12 ng/ml), vitamin D insufficiency group (12-20 ng/ml), and vitamin D sufficiency group (>20 ng/ml). Serum 1-25(OH) D3, blood eosinophil, total IgE, dermatophagoides pteronyssinus (Dp), and dermatophagoides farina (Df) specific IgE (sIgE) were detected, and questionnaires of symptom and medication scores were collected before and after one year of treatment. After one year of SCIT treatment, the symptom and medication score significantly decreased (P < 0.05), but there was no difference between the efficacy in different groups (P > 0.05). Our study found a statistical difference in Dp sIgE level between the vitamin D deficiency and the sufficiency groups (P = 0.024), and vitamin D levels become lower with children's growth (Y = -0.8981*X + 34.26, P = 0.0025). No difference was found between the efficacy of one-year SCIT and serum vitamin D levels based on symptom and medication scores. Nevertheless, higher vitamin D levels may be associated with a decreased indicator of Dp allergy.

IMMUNOMODULATORY MECHANISMS OF GRASS ALLERGEN IMMUNOTHERAPY ON DIFFERENTIAL T CELLS TRANSCRIPTOME POLARIZATION IN EXPLORATORY TRIAL

<h3>Introduction</h3> A short pre-seasonal course of grass subcutaneous immunotherapy (SCIT) using MicroCrystalline Tyrosine (MCT) and Monophosphoryl Lipid A showed a significant improvement in combined symptom and medication scores (CSMS) in an exploratory field study (PQGrass309). Moreover, molecular mechanisms associated clinical benefit remain to be fully determined. <h3>Methods</h3> Peripheral blood mononuclear cells were obtained from participants, who underwent subcutaneous grass immunotherapy or placebo with MCT at baseline, end of treatment and end of grass pollen season (GPS). A panel of 58 genes was profiled. Ingenuity Pathway Analysis was deployed to elucidate molecular signature and functional relationships for observed gene expression. <h3>Results</h3> CSMS was significantly decreased (-33%) following grass SCIT compared to placebo with MCT. Transcriptome profiling showed transient upregulation of Th2/Th2A and Th17 signature cytokines at the start of GPS and steady downregulation at the end of GPS. Immune modulation towards Th1/Treg at pre-GPS and post-GPS with upregulation of IFNγ, IL-12A, EBI3 (IL-35), IL-27, IL-10, TGFβ was indicative of immune tolerance induction. T helper cell differentiation was one of the most significantly enriched pathways with Th17 mapped as a top enriched canonical pathway, which was transiently upregulated at the start of GPS and downregulated at the end of GPS. Upstream regulator analysis predicted IL-4, IL17A/IL17F, IL-13 and IFNγ as top upstream regulators at pre-GPS and IFNγ, IL-12A, IL-27 at post-GPS. <h3>Conclusion</h3> A distinct immunomodulatory profile of grass SCIT induced responses revealed clusters of differentially expressed genes, which supports restoration of the Th1/Th2 balance and provides the underpinning mechanisms associated with the robust clinical efficacy outcome.

INCREASING THE PERCENTAGE OF PATIENTS THAT RECEIVE THE INFLUENZA VACCINE IN ALLERGY SHOT CLINICS

<h3>Introduction</h3> Vaccinations are a critical component of routine healthcare, and studies reveal that patients are more likely to receive vaccinations when they are recommended by a medical provider. In the US, annual influenza vaccine rates were 48.4% during the 2019-20 influenza season and 50.2% during the 2020-21 influenza season. The US Healthy People 2030 target goal is 70%. <h3>Methods</h3> As part of a quality improvement program during the COVID-19 pandemic, subcutaneous immunotherapy (SCIT) patients were screened at every injection visit for administration of the 2021-22 influenza vaccine. A sticker was placed in the injection room to remind staff to assess status. Vaccine currency was documented on the patients' injection record. The vaccination rate for the 2020-21 flu season was compared to the vaccination rate for the 2021-22 flu season. <h3>Results</h3> 175 patients (172 SCIT and 3 biologic) were given injections and screened for the influenza vaccine during the period of September 1, 2021 to May 24, 2022. Of the 175 patients, 87.4% of patients received the influenza vaccination (153 vaccinated and 22 declined). The 2020-21 vaccination rate in the clinic was 91.7%. <h3>Conclusion</h3> Allergy clinics have a captive audience in their injection rooms with SCIT patients to screen for the influenza vaccine. Our simple screening program resulted in an unprecedented influenza vaccination rate of 87.4% during the 2021-22 influenza season and 91.7% during the 2020-21 influenza season. Each year, our program produced an influenza vaccination rate nearly double the national average. Allergists should consider implementing a similar injection room system for influenza vaccine screening.

DELAYED TYPE HYPERSENSITIVITY IN A TRICENARIAN WITH SKIN PRICK TESTING

<h3>Introduction</h3> A rare, adverse event of skin prick testing (SPT) is the development of a delayed hypersensitivity reaction (DTH). The features and pattern of this reaction are likely reflective of a Th1 immune response in which CD8+ T cells in the epithelial cells are pre-sensitized to the antigen, resulting in cell-mediated toxicity. <h3>Case Description</h3> A female allergist in her 30s with a history of allergic rhinitis and atopic dermatitis had aeroallergen SPT performed in clinic that was prompted by a noticed discrepancy between multi-prick and single prick application of the positive control despite the test being administered by the same nurse.The SPT was performed on the forearm using the ComforTen Skin Test System and QuinTip with extracts prepared by HollisterStier. At 15 minutes following placement, histamine, cat, and dust mite were positive. Over days and weeks, the allergist noticed persistent wheals and erythema at the prick sites of cat and dust mite, consistent with a DTH. Prior to this, she had had two SPTs performed, one in 2016 and the other in 2017, without adverse events. She has never been treated with subcutaneous immunotherapy (SCIT). <h3>Discussion</h3> It is evident based on the nature of this reaction that our patient developed a DTH to SPT. Patients who develop DTH reactions to skin prick testing can be symptomatically treated with topical steroids. It is currently recommended that SCIT be avoided in patients who develop DTH to prevent similar reactions following immunotherapy injections.

HYPERSENSITIVITY REACTION TO DUST MITE IMMUNOTHERAPY FOLLOWING SHELLFISH INGESTION

<h3>Introduction</h3> Immediate hypersensitivity reactions are an occasional side effect of allergen immunotherapy. Patients develop severe allergic symptoms within half-hour after receiving allergen immunotherapy. Symptoms range from mild, local to severe systemic reaction. Patients with House Dust Mite (HDM) allergy can be sensitized to shrimp due to the phylogenetic similarity attributable to tropomyosin. We report a patient who developed anaphylactic symptoms from HDM immunotherapy correlated with shrimp ingestion hours prior to receiving immunotherapy. <h3>Case Description</h3> A 35 year-old male asthmatic with allergic rhinosinusitis, tested positive for Dermatophagoides farinae and D. pteronyssinus, was started on Subcutaneous Immunotherapy (SCIT) for HDM. Following routine buildup, he received appropriate maintenance dosage every three weeks for 1.5 years with excellent symptom control. However, on three occasions, he developed systemic symptoms within 30 minutes post-immunotherapy, developing acute shortness of breath, widespread urticaria, itching, and light-headedness. He was treated appropriately. Questioning revealed that the SCIT reactions coincided with days the patient had eaten shrimp earlier. Skin-testing to shellfish was mildly positive to shrimp and negative to other crustaceans. Patient was advised to avoid ingesting all crustaceans on the day of immunotherapy. Subsequent three years on immunotherapy have been without incident. <h3>Conclusion</h3> <b>:</b> Among patients receiving HDM immunotherapy, it may be prudent to avoid cross-reactive foods like shellfish due to increased likelihood of allergic reactions to synergistic allergens. This expression is also likely during sublingual immunotherapy for HDM. We suggest evaluating crustacean allergy status for all patients contemplating HDM immunotherapy, and avoiding ingestion of crustaceans the same day as treatment, to forestall potential hypersensitivity reactions.

EFFICACY OF HOUSE DUST MITE IMMUNOTHERAPY IN PATIENTS WITH ATOPIC AND CONTACT DERMATITIS OVERLAP SYNDROME

<h3>Introduction</h3> Allergen-specific immunotherapy may modify chronic inflammation in patients with allergic overlap syndrome, including atopic dermatitis and contact allergy. <h3>Methods</h3> A randomized, double-blind, placebo-controlled study was conducted. 81 patients aged 18 to 60 years with atopic and contact dermatitis were included. The main criterion for inclusion in the studies was confirmation of sensitization to house dust mites and contact allergy. Patients with a SCORAD index greater than/equal to 15 points were included. The primary endpoint of efficacy was a significant reduction in the SCORAD index between the active and placebo groups by more than 12 points after 6 months of treatment. Contact allergy was confirmed by skin patch tests. Specific IgE to Der p1 and Der p 2 were determined by ELISA. <h3>Results</h3> 71 patients completed the study, with 36 patients in the active group and 35 in the placebo group. Patients in both groups received standard treatment. Patients in the active group received subcutaneous allergen-specific immunotherapy with house dust mite extracts. In the active group, a decrease in the SCORAD index by 12 points was recorded in 30 of 36 patients, which significantly differed (chi squared 5.71, p<0.017) from the placebo group, where the decrease in the index occurred in 19 of 35 patients. The number of exacerbations of contact allergy in the active group was significantly less (p<0.05) compared with the placebo group. <h3>Conclusion</h3> This pilot study confirmed that allergen-specific immunotherapy may be effective in the overlap syndrome of atopic and contact dermatitis.

IMPROVEMENT OF SEVERE ATOPIC DERMATITIS AND POST-INFLAMMATORY HYPERPIGMENTATION IN A HISPANIC PATIENT TREATED WITH DUPILUMAB

<h3>Introduction</h3> Atopic dermatitis (AD) is a common chronic disease characterized by severe itching associated with recurrent eczematous lesions and has an enormous impact on patients' quality of life. Dupilumab, is the first biological agent approved for patients with moderate-to-severe AD. <h3>Case Description</h3> A 16-year-old male patient was evaluated in the allergy clinic at the age of 12, for eczema and chronic rhinitis. He developed eczema and nasal symptoms during childhood and despite an excellent adherence to treatment with topical steroids and moisturizers, there was no improvement. The patient presented severe generalized AD lesions and hyperpigmentation with a SCORAD of 56.8. During his evaluation, he resulted with positive skin prick tests to <i>Bromus spp., Cynodon dactylon, Holcus lanatus, Phleum pratense, Fraxinus americana, Prosopis spp. and Dermatophagoides pteronyssinus</i>. Subcutaneous (SC) immunotherapy was initiated along with a short course of oral and topical steroids, as well as skincare. However, he presented poor control of symptoms and poor quality of life, oral cyclosporine was started for 11 months. Despite treatment he continued with severe AD, cyclosporine was tapered to start management with dupilumab. Dupilumab was started at an initial dose of 600 mg SC, subsequently 300 mg SC every 2 weeks, presenting improvement in hyperpigmentation, pruritus and xerosis. Currently he has a SCORAD of 3.5 without any adverse effects to dupilumab. <h3>Discussion</h3> Dupilumab improves pruritus, quality of life and like in this case, may return the patient´s original skin tone after post-inflammatory hyperpigmentation occurs due to AD. This biological agent is the preferred treatment for moderate-to-severe AD. Clinical evolution of an adolescent with severe atopic dermatitis and use of dupilumab. A y C) Before treatment with dupilumab, severe generalized atopic dermatitis lesions and hyperpigmentation, B y D) After 10 months of treatment with dupilumb, improvement of atopic dermatitis and postinflammatory hyperpigmentation

AN UNUSUAL CASE OF CHRONIC RHINOSINUSITIS

<h3>Introduction</h3> We present a case of long-standing nasal symptoms initially suggestive of chronic rhinosinusitis with nasal polyposis (CRSwNP) but later found to be an atypical etiology. <h3>Case Description</h3> A 30 year-old female with past medical history of tobacco use disorder presented with two years of nasal congestion, rhinorrhea, and lost of taste and smell. She was trialed on diphenhydramine, loratidine, fexofenadine, cetirizine, and intranasal budesonide without significant relief. She had history of ENT provocation testing positive for tree, weeds, grass pollen, mold, dust mite and pet dander and was started on subcutaneous allergy immunotherapy without improvement. Additional history was notable for mild eosinophilia of 300 cells/μL and vomiting and nasal congestion to tramadol and naproxen - though tolerated other NSAIDs. She was evaluated by ENT where she was found to have large nasal polyps via rhinoscopy and diagnosed with CRSwNP. A referral to Allergy was made for consideration of dupilumab therapy. However, CT scan showed large mass eroding into nearby facial sinuses. There was also notable increased bone growth along right middle turbinate initially suggestive of inverted papilloma. Pathology showed invasive poorly differentiated non-keratinizing squamous cell carcinoma positive for HPV. Definitive treatment involved multiple debulking procedures and adjuvant radiation. <h3>Discussion</h3> This case highlights the typical treatment of chronic rhinosinusitis with nasal polyposis as well as the broad differential required of her presenting symptoms. Her symptoms were very suggestive of chronic sinusitis with nasal polyposis, but treatment was resistant. Other etiologies of nasal polyps, including malignancy, should be on differential of recalcitrant nasal symptoms.

ENVIRONMENTAL FACTORS INFLUENCING SYMPTOMS AND USE OF RELIEF MEDICATIONS IN SUBJECTS WITH SEASONAL ALLERGIC RHINOCONJUNCTIVITIS

<h3>Introduction</h3> In Phase III Allergen Immunotherapy (AIT) trials, the underlying assumption is that there is a causal relation between symptoms and allergen burden. However, there is a more complex interplay of allergen exposure and environmental variables. We report on a study where the impact of environmental factors has prospectively been taken into account to evaluate their impact on AIT treatment effects. <h3>Methods</h3> An exploratory field study comparing the efficacy of a modified grass subcutaneous immunotherapy product using MCT and MPL as adjuvant system (PQ Grass) versus placebo in subjects with allergic rhinitis/rhinoconjunctivitis was performed. The combined symptom and medication score (CSMS) during the peak grass pollen season was the primary endpoint. The daily pollen exposure as well as daily ozone and humidity levels were also collected. An exploratory analysis was defined using a hierarchical linear mixed model to evaluate the influence of these environmental variables on the primary endpoint results using observed cases. <h3>Results</h3> A statistically significant influence of daily humidity (p<0.001) in addition to the daily pollen burden on CSMS was demonstrated. When correcting the primary endpoint for these environmental factors the average CSMS improvement after PQ grass compared to placebo improved from 39.5% (based on the primary analysis model) without adjustment for environmental factors to 55.6% with adjustment (p<0.001) (observed cases). <h3>Conclusion</h3> Environmental conditions have an influence on the severity of the CSMS and correcting for these influences by introducing these as covariates may improve the primary outcome of Phase III AIT field studies.

Lack of Harmonized Adherence Criteria in Allergen Immunotherapy Prevents Comparison of Dosing and Application Strategies: A Scoping Review

Allergen immunotherapy (AIT) involves the application of increasing doses of allergen extract (as oral, sublingual, or subcutaneous immunotherapy) until immunologic tolerance is reached. Successful AIT relies on the consistent administration of allergen extract; therefore, adherence to these treatments is vital for compelling long-term results. Our review discusses the current terminology from adherence research in general, summarizes 25 current studies on adherence research in AIT in a scoping literature review, and delineates recommendations for tools and parameters for adherence research, aiming to improve outcomes in AIT. Almost every adherence study in AIT published to date used different tools, parameters, and data sources for measuring adherence and persistence rates. Unfortunately, an easily accessible, objective parameter or biomarker for monitoring treatment adherence and success has not yet been established for AIT. This situation calls for the development of an international core outcomes set for AIT that defines what is exactly meant by AIT adherence and how AIT adherence should be consistently measured. Therefore, we exemplarily present results and conclusions from adherence research in chronic diseases other than allergology. We aim to facilitate the development of advanced methods, considering the challenging disease specificities of these parameters in a routine care setting of AIT.

Effects of combination treatment with tezepelumab and allergen immunotherapy on nasal responses to allergen: A randomized controlled trial

Thymic stromal lymphopoietin (TSLP) has been shown to play a central role in the initiation and persistence of allergic responses. We evaluated whether tezepelumab, a human monoclonal anti-TSLP antibody, improved the efficacy of subcutaneous allergen immunotherapy (SCIT) and promoted the development of tolerance in patients with allergic rhinitis. We conducted a double-blind parallel design trial in patients with cat allergy. Atotal of 121 patients were randomized to receive either intravenous tezepelumab plus subcutaneous cat SCIT, cat SCIT alone, tezepelumab alone, or placebo for 52 weeks, followed by 52 weeks of observation. Nasal allergen challenge (NAC), skin testing, and blood and nasal samples were obtained throughout the study. At week 52, the NAC-induced total nasal symptom scores (TNSS) (calculated as area under the curve [AUC0-1h] and as peak score [Peak0-1h] during the first hour after NAC) were significantly reduced in patients receiving tezepelumab/SCIT compared to SCIT alone. At week 104, one year after stopping treatment, the primary end point TNSS AUC0-1h was not significantly different in the tezepelumab/SCIT group compared to SCIT alone, while TNSS Peak0-1h was significantly lower in those receiving combination treatment versus SCIT. Transcriptomic analysis of nasal epithelial samples demonstrated that treatment with the combination of SCIT/tezepelumab, but neither monotherapy, caused persistent downregulation of a gene network related to type 2 inflammation that was associated with improvement in NAC responses. Inhibition of TSLP augments the efficacy of SCIT during therapy and may promote tolerance after a 1-year course of treatment. (ClinicalTrials.gov NCT02237196).

Betv1-displaying elastin-like polypeptide nanoparticles induce a strong humoral and weak CD4+ T-cell response against Betv1 in a murine immunogenicity model.

There is growing concern about the toxicity of colloidal aluminum salts used as adjuvants in subcutaneous allergen immunotherapy (SCIT). Therefore, alternative adjuvants and delivery systems are being explored to replace alum in SCIT. We applied micellar elastin-like polypeptides (ELPs), a type of self-assembling protein, to replace alum as vaccine adjuvant in birch pollen SCIT. ELP and an ELP-Bet v 1 fusion protein were expressed in E. coli and purified by immuno-affinity chromatography and inverse-transition cycling (ITC). Nanoparticles self-assembled from ELP and a 9:1 ELP/ELP-Bet v 1 mixture were characterized by using dynamic light scattering and atomic force microscopy. Allergenicity was assessed by measuring mediator release from rat basophilic leukemia cells transformed with the human FcϵR1 and sensitized with sera derived from human birch pollen allergic patients. Humoral and T-cell immunity were investigated by immunizing naïve mice with the ELP/ELP-Bet v 1 nanoparticles or alum-adsorbed Bet v 1, both containing 36 µg Bet v 1. ELP and ELP/ELP-Bet v 1 self-assembled at 37°C into spherically shaped micelles with a diameter of ~45 nm. ELP conjugation made Bet v 1 hypo-allergenic (10-fold). Compared to alum-adsorbed Bet v 1, ELP/ELP-Bet v 1 nanoparticles induced stronger IgG responses with an earlier onset. Additionally, ELP/ELP-Bet v 1 did not induce Th2 skewing cytokines and IgE. The hypoallergenic character and strong humoral immune response in the absence of a Th2-skewing T-cell response make ELP-based nanoparticles a promising candidate to replace alum in SCIT.

Subcutaneous birch pollen allergen immunotherapy with a depigmented polymerized extract shows only sustained and long-term efficacy in a subgroup of monosensitized adults and adolescents with allergic rhinitis.

BackgroundAllergen immunotherapy (AIT) is an approved treatment for seasonal respiratory allergic diseases. A depigmented polymerized birch pollen extract for subcutaneous allergen immunotherapy (SCIT) has been demonstrated to be efficacious and safe in patients allergic to birch pollen and its homologous group.ObjectiveTo determine whether SCIT with a birch pollen formulation (5000 depigmented polymerized (DPP) units/mL) shows sustained and long‐term efficacy in adults and adolescents with birch‐pollen induced allergic rhinitis with or without intermittent asthma.MethodsA multicentre (n = 66), double‐blind, placebo‐controlled Phase III clinical trial was performed in the Czech Republic, Finland, Germany, Latvia, Lithuania, Poland and Russia. Participants were randomized 2:1 to active treatment (birch 5000 DPP/ml) or placebo for three years of SCIT and followed up for two treatment‐free years. The primary efficacy endpoint was the EAACI's combined symptom and medication score for rhinoconjunctivitis (CSMSEAACI).ResultsA total of 973 participants were screened and 649 were randomized (active treatment: n = 434; placebo: n = 215). The intention‐to‐treat analysis of the CSMSEAACI in the overall study population did not demonstrate statistically significant differences in years 1, 2 and 3. In a post‐hoc analysis, among the subgroup of patients monosensitized to birch pollen allergen only (n = 200), we observed a statistically significant difference (active treatment vs. placebo) in the CSMSEAACI in year 2, 3 and 5. The AIT's safety profile was good.ConclusionsSCIT with a depigmented polymerized birch pollen extract was safe. Sustained and long‐term efficacy in years 2, 3 and 5 in monosensitized patients, but not in polysensitized patients was demonstrated.(EudraCT 2012‐000414‐11)

Allergen immunotherapy for atopic dermatitis: Systematic review and meta-analysis of benefits and harms

Atopic dermatitis (AD, eczema) is driven by a combination of skin barrier defects, immune dysregulation, and extrinsic stimuli such as allergens, irritants, and microbes. The role of environmental allergens (aeroallergens) in triggering AD remains unclear. We systematically synthesized evidence regarding the benefits and harms of allergen immunotherapy (AIT) for AD. As part of the 2022 American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters AD Guideline update, we searched the MEDLINE, EMBASE, CENTRAL, CINAHL, LILACS, Global Resource for Eczema Trials, and Web of Science databases from inception to December 2021 for randomized controlled trials comparing subcutaneous immunotherapy (SCIT), sublingual immunotherapy (SLIT), and/or no AIT (placebo or standard care) for guideline panel-defined patient-important outcomes: AD severity, itch, AD-related quality of life (QoL), flares, and adverse events. Raters independently screened, extracted data, and assessed risk of bias in duplicate. We synthesized intervention effects using frequentist and Bayesian random-effects models. The GRADE approach determined the quality of evidence. Twenty-three randomized controlled trials including 1957 adult and pediatric patients sensitized primarily to house dust mite showed that add-on SCIT and SLIT have similar relative and absolute effects and likely result in important improvements in AD severity, defined as a 50% reduction in SCORing Atopic Dermatitis (risk ratio [95% confidence interval] 1.53 [1.31-1.78]; 26% vs 40%, absolute difference 14%) and QoL, defined as an improvement in Dermatology Life Quality Index by 4 points or more (risk ratio [95% confidence interval] 1.44 [1.03-2.01]; 39% vs 56%, absolute difference 17%; both outcomes moderate certainty). Both routes of AIT increased adverse events (risk ratio [95% confidence interval] 1.61 [1.44-1.79]; 66% with SCIT vs 41% with placebo; 13% with SLIT vs 8% with placebo; high certainty). AIT's effect on sleep disturbance and eczema flares was very uncertain. Subgroup and sensitivity analyses were consistent with the main findings. SCIT and SLIT to aeroallergens, particularly house dust mite, can similarly and importantly improve AD severity and QoL. SCIT increases adverse effects more than SLIT. These findings support a multidisciplinary and shared decision-making approach to optimally managing AD.

Long-term adherence to imported fire ant subcutaneous immunotherapy

BackgroundImported fire ant (IFA) whole-body extract subcutaneous immunotherapy (IT) is a safe and effective treatment for IFA hypersensitivity, with a recommended length of treatment of 3 to 5 years. ObjectiveTo evaluate long-term IFA IT adherence in patients with IFA allergy living in an endemic area. MethodsDuring 2007 to 2014, patients with IFA-sting systemic reactions and a recommendation to start IFA IT were prospectively enrolled in this study. Subjects were contacted annually for interval IT adherence. Institutional review board approval was obtained. ResultsA total of 87 subjects, ages 2 to 64 years, with a recommendation to initiate IFA IT, were enrolled. Subjects were predominantly adult (76%) and female (55%), and 30% had asthma. Of these patients, 77 (89%) initiated treatment within 1 year of recommendation; 18 (23%) adhered to a 3-year course; and 10 (13%) adhered to a 5-year course. At 3 years, there were no significant differences in adherence between male and female subjects (28% vs 19%, P = .33), children and adults (25% vs 22%, P = .79), or those with or without asthma (30% vs 20%, P = .31). Adherence in subjects with mild initial reactions was lower than in subjects with moderate-to-severe reactions (0% vs 25%, P = .05) at 3 years only. Conventional buildup and concurrent flying Hymenoptera venom immunotherapy were predictive of adherence. Reasons for discontinuation were relocation to a nonendemic area (29%) and inconvenience (27%). ConclusionThis study showed poor long-term adherence to IFA IT at 3 and 5 years. Initial sting severity, buildup protocol, and concurrent flying Hymenoptera venom immunotherapy were predictors for long-term IT adherence.

Induction of food-specific IgG by Gene Gun-delivered DNA vaccines

Shellfish and tree nut allergies are among the most prevalent food allergies, now affecting 2%-3% and 1% of the US population, respectively. Currently, there are no approved therapies for shellfish or tree nut allergies, with strict avoidance being the standard of care. However, oral immunotherapy for peanut allergy and subcutaneous immunotherapy for environmental allergens are efficacious and lead to the production of allergen-specific IgG, which causes suppression of allergen effector cell degranulation. Since allergen-specific IgG is a desired response to alleviate IgE-mediated allergies, we tested transcutaneously-delivered DNA vaccines targeting shellfish and tree nut allergens for their ability to induce antigen-specific IgG, which would have therapeutic potential for food allergies. We assessed Gene Gun-delivered DNA vaccines targeting either crustacean shellfish or walnut/pecan allergens, with or without IL-12, in naïve mice. Three strains of mice, BALB/cJ, C3H/HeJ and CC027/GeniUnc, were evaluated for IgG production following vaccination. Vaccines were administered twice via Gene Gun, three weeks apart and then blood was collected three weeks following the final vaccination. Vaccination with shellfish allergen DNA led to increased shrimp-specific IgG in all three strains, with the highest production in C3H/HeJ from the vaccine alone, whereas the vaccine with IL-12 led to the highest IgG production in BALB/cJ and CC027/GeniUnc mice. Similar IgG production was also induced against lobster and crab allergens. For walnut/pecan vaccines, BALB/cJ and C3H/HeJ mice produced significantly higher walnut- and pecan-specific IgG with the vaccine alone compared to the vaccine with IL-12, while the CC027 mice made significantly higher IgG with the addition of IL-12. Notably, intramuscular administration of the vaccines did not lead to increased antigen-specific IgG production, indicating that Gene Gun administration is a superior delivery modality. Overall, these data demonstrate the utility of DNA vaccines against two lifelong food allergies, shellfish and tree nuts, suggesting their potential as a food allergy therapy in the future.