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Background: The impact of allergic rhinoconjunctivitis on the early (EAR) and late asthmatic response (LAR) has yet to be assessed during optimal allergen exposure conditions., Objective: We aimed to assess predictive factors of the EAR and LAR and to evaluate the relation between rhinitis, conjunctivitis and asthma induced by cat allergen exposure in an environmental exposure chamber (EEC)., Methods: Data from two cohort studies involving asthmatic patients with cat allergy who performed a cat allergen exposure challenge in ALYATEC EEC were analysed. Spirometry, visual analogue scale (VAS) for asthma, VAS for rhinitis, Total Nasal Symptoms Score, Total Ocular Symptoms Score (TOSS), Rhinoconjunctivitis Total Symptoms Score and Abelson score were used to assess asthma, rhinitis and conjunctivitis during and after exposure., Results: An EAR occurred in 65.1% of patients, 32.1% of whom had a LAR. The diameter of the prick test to cat allergens and non-specific bronchial hypersensitivity level were independent risk factors for EAR (p < .05). No independent risk factors for LAR were identified. Rhinoconjunctivitis severity during exposure correlated with the asthma VAS during EAR and LAR (p < .05). Allergen exposure time needed to trigger an EAR correlated with the Abelson score during exposure (p < .05). The asthma VAS and TOSS during exposure correlated with faster LAR occurrence (p < .05)., Conclusion: Prick test size and non-specific bronchial hypersensitivity level were confirmed as independent predictive factors of EAR during allergen exposure in an EEC. This study demonstrated the relation between the severity of rhinitis, conjunctivitis and asthma induced by allergen exposure for both EAR and LAR., (© 2024 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

We investigated the relationship between subjective symptoms and objective findings in patients with allergic conjunctival diseases (ACD) and test results for tear total IgE (t-tIgE), conjunctival eosinophils (c-Eo), serum total IgE (s-tIgE), serum-antigen specific IgE (s-sIgE), and serum eosinophils (s-Eo). Subjective symptoms and objective findings of patients with ACD were evaluated using Japanese Allergic Conjunctival Disease Quality of Life Questionnaire (JACQLQ), which described disability score and emotional score written by patient and clinical findings score written by ophthalmologist. We investigated the relationship between questionnaire scores and laboratory data for t-tIgE, c-Eo, s-tIgE, s-sIgE, and s-Eo. Scores of impediments to life and of moods were highest in vernal keratoconjunctivitis among ACD. Cases with positive pollen-sIgE showed significantly more nasal symptom score than those with negative pollen-sIgE (P < 0.05). Cases with positive t-tIgE or c-Eo showed significantly more objective symptoms' JACQLQ score than those with negative t-tIgE or c-Eo (P < 0.05), respectively. Cases positive for house dust/mite-sIgE, showed significantly more objective symptoms' JACQLQ score than those without for house dust/mite-sIgE (P < 0.05). These results indicate that ACD could be analyzed more accurately by the combination of JACQLQ and laboratory data., (© 2024. The Author(s).)

Purpose of Review: The aim of this review, is to present an updated revision of topical management of SAC and PAC, based on the available scientific evidence and focused on the impact of ophthalmic solution formulations on eye surface., Recent Findings: Physicians treating ocular allergy should be aware of tear film and tear film disruption in SAC and PAC, and how eye drop composition and additives affect the physiology of the allergic eye. Seasonal and perennial allergic conjunctivitis (SAC and PAC) are the most frequent causes of ocular allergy (OA), and both conditions are underdiagnosed and undertreated. SAC and PAC are immunoglobulin E (IgE)-mediated hypersensitivity reactions. The additional tear film disruption caused by the release of inflammatory mediators increases and exacerbates the impact of signs and symptoms and may trigger damage of the ocular surface. Comorbidities are frequent, and dry eye disease in particular must be considered. Clinical guidelines for the management of SAC and PAC recommend topical therapy with antihistamines, mast cells stabilizers or dualaction agents as first-line treatment, but care should be taken, as many medications contain other compounds that may contribute to ocular surface damage., (© 2024. The Author(s).)

Allergic conjunctival disease is an immune-mediated inflammatory disease of the conjunctiva. To develop clinically useful drugs, it is necessary to develop quantitative evaluation methods that reflect the clinical symptoms in experimental animal models. Allergic conjunctivitis model mice were systemically sensitised with ovalbumin (OVA) administered intraperitoneally and locally sensitised with OVA eye drops between day 14-28. Next, conjunctivitis induced by ocular administration of OVA solution to sensitised mice was evaluated based on tear volume. Additionally, we evaluated increase in tear volume induced by direct ocular instillation of histamine, compound 48/80, and carrageenan. An increase in antigen-induced tear volume was observed in the mice model. Additionally, direct instillation of histamine, compound 48/80, and carrageenan increased tear volume. Furthermore, levocabastine inhibited the increase in tear volume in antigen-induced allergic conjunctivitis and histamine- and compound 48/80-induced conjunctivitis models. In contrast, betamethasone suppressed carrageenan-induced tear volume but not histamine- or compound 48/80-induced tear volume. Histamine may be involved in increased tear volume in allergic conjunctivitis. Betamethasone is not directly involved in the action of histamine and is thought to suppress increase in tear volume. Evaluation of tear volume in a conjunctivitis mice model is highly quantitative; therefore, it is possible to evaluate drug efficacy. This is considered a useful index compared with conventional methods., Competing Interests: Declaration of competing interest All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Myopia is regarded as a worldwide epidemic ocular disease, has been proved related to inflammation. CD55, also known as decay-accelerating factor (DAF) can modulate the activation of complement through inhibiting the formation of complement 3 convertase and its dysregulation is involved in various inflammatory diseases. To investigate the association between CD55 and myopia, and to test whether CD55 can inhibit myopia development by suppressing inflammation in the eye, we use three different animal models including monocular form-deprivation myopia, myopia induced by TNF-α administration and allergic conjunctivitis animal model to reveal the CD55 in myopia development. The tears of thirty-eight participants with different spherical equivalents were collected and CD55 in the tears were also analyzed. Complement 3 and complement 5 levels increased while CD55 levels decreased in allergic conjunctivitis and myopic eyes. After anti-inflammatory drugs administration, CD55 expression was increased in monocular form-deprivation myopia model. We also found inflammatory cytokines TGF-β, IL-6, TNF-α, and IL-1β may enhance complement 3 and complement 5 activation while CD55 level was suppressed contrary. Moreover, lower CD55 levels were found in the tears of patients with myopia with decreased diopter values. Finally, CD55-Fc administration on the eyelids can inhibit the elongation of axial length and change of refractive error. CD55-Fc application also suppress myopia development subsequent to complement 3 and complement 5 reduction and can lower myopia-specific (MMP-2 and TGF-β) cytokine expression in TNF-α induced myopia animal model. This suggests that CD55 can inhibit myopia development by suppression of complement activation and eventual down-regulation of inflammation., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The clinical development program of the SQ grass, ragweed, tree, and house dust mite (HDM) sublingual immunotherapy (SLIT)-tablets for allergic rhinitis/conjunctivitis (AR/C) included clinical trials conducted in North America, Europe, and Japan. Objective: Data from these trials were analyzed to assess efficacy, immunologic mechanisms, and safety outcomes across allergens and geographic regions. Methods: Thirteen phase III, double-blind, placebo controlled trials in the subjects with AR/C were conducted in North America, Europe (including Russia), and Japan (N = 7763 analyzed). Trials were generally similar with respect to medical practice, target population, eligibility criteria, and efficacy and safety monitoring. Data were analyzed for the approved doses in North America and Europe. Four statistical models were used to enhance comparison of the efficacy end points among the trials. Results: The SLIT-tablets demonstrated consistent efficacy across allergens and regions, regardless of the statistical analysis used. Relative improvement in the primary efficacy end point compared with placebo by using the predefined protocol analysis ranged from 17.9% to 32.8%, 17.5% to 19.3%, 20.6% to 38.3%, and 39.6% with the grass, HDM, ragweed, and tree SLIT-tablets, respectively. The kinetics of specific immunoglobulin E (IgE) and IgG4 responses were similar among the allergens and regions. Local application-site reactions were the most common adverse events for all allergens and in all regions. Most treatment-related adverse events for all allergens and in all regions were mild in severity. The rate of systemic allergic reactions was similar across regions (0%-0.54%). Conclusion: Confirmatory phase III trials for SLIT-tablets in the treatment of AR/C showed consistent efficacy, immunologic, and safety outcomes across allergens and geographic regions.

Purpose of Review: Integrative medicine techniques are increasingly accepted into the treatment paradigm for many chronic disorders including eye disease. Over 71% of patients, including 67% of those with eye disorders, use some form of Integrative therapy. Physicians should be well versed in evidence-based therapies to know how to refer patients for the best complimentary care. We highlight the most effective integrative therapeutics from different complementary treatment paradigms to offer a framework for approaching therapy in patients with ocular surface disorders (OSDs)., Recent Findings: Lifestyle and behavioral modifications help a proportion of people with OSDs like dry eye disease and allergic conjunctivitis, which are interrelated disorders. Nutrition and supplementation can also play a role in addressing underlying inflammation and improving OSD symptoms. Acupuncture and traditional herbal medicine may also benefit some patients. New technologies offer innovative treatment pathways in the treatment of OSD but require referral to Ocular Surface Treatment Centers., Summary: Integrative treatment approach for OSD incorporates allopathic medicine, traditional remedies and lifestyle behavioral interventions, Ayurveda and herbal medicine, Nutritional Supplements, Homeopathy, Acupuncture and Chinese Medicine. New cutting-edge technologies offer breakthroughs in difficult to treat ocular surface cases. Collaboration between allergy or otolaryngology offices, complementary practitioners, as well as optometrists and ophthalmologists in Ocular Surface Treatment Centers can offer patients new avenues of treatment., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Allergic conjunctivitis is characterized by the development of pathophysiological changes to the ocular surface, which occurs when pro-allergic and pro-inflammatory mediators interact with their cognate receptors expressed on immune and nonimmune cells. Traditional treatments with antihistamines and corticosteroids provide relief, but there is a need for more efficacious and tolerable long-term therapy with a better safety profile. This article aims to provide an overview of the mode of action and clinical application of agonist therapies targeting glucocorticoid, melanocortin, and toll-like receptors, as well as antagonist therapies targeting cytokine, chemokine, integrin, and histamine receptors., Recent Findings: There has been considerable advancement in immunology and pharmacology, as well as a greater understanding of the cellular and molecular mechanisms of allergic conjunctivitis. Recent research advancing therapy for allergic conjunctivitis has focused on developing synthetic molecules and biologics that can interfere with the process of the allergic immune reaction., Summary: This review discusses novel therapeutic receptors being explored agonistically or antagonistically to develop alternative treatment options for allergic conjunctivitis. These novel approaches hold promise for improving the management of allergic eye diseases, offering patients hope for more effective and safer treatment options in the future., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Allergic rhinitis with or without conjunctivitis can negatively impact many aspects of quality of life (QoL). The efficacy and safety of standardized quality (SQ) sublingual immunotherapy (SLIT) tablets have been confirmed across large clinical trials in adults with grass, tree, ragweed, and house dust mite (HDM) allergic rhinitis with or without conjunctivitis., Objective: This pooled analysis investigates whether the reduction in symptom burden found across the clinical trials is supported by improvements in QoL., Methods: A total of 11 phase II/III randomized placebo-controlled trials across the SQ grass, tree, ragweed, and HDM SLIT tablets (grass: N = 3179; ragweed: N = 767; tree: N = 634; HDM: N = 2221) were included. QoL was assessed using the standardized Rhinitis Quality of Life Questionnaire (RQLQ), with the exception of 3 grass trials, which used the nonstandardized version. The overall RQLQ scores were expressed as a mean of 7 domains. In the pooled analysis, treatment was used as fixed effect; and the trial, and the interaction between region/country and trial as random effects., Results: The pooled analysis showed consistent and statistically significant improvements in overall RQLQ scores across all 4 SQ SLIT tablets versus placebo (pooled estimate [95% CI], P value-grass: -0.20 [-0.28 to -0.12], P < .001; tree: -0.42 [-0.58 to -0.26], P < .001; ragweed: -0.36 [-0.55 to -0.17], P < .001; HDM: -0.28 [-0.39 to -0.17], P < .001). Furthermore, significant improvements versus placebo for all 4 SQ SLIT tablets were seen across the 7 individual domains., Conclusions: The proven efficacy of SQ SLIT tablets to reduce symptoms across 4 of the most common respiratory allergens is supported by concurrent significant improvements in RQLQ scores overall and for all 7 domains., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Allergen immunotherapy (AIT) is a recognized key therapeutic modality for the treatment of allergic respiratory disease. Definitive studies have provided evidence-based data to demonstrate its effectiveness in allergic rhinitis and asthma due to the inhalation of proteinaceous allergic substances from specific seasonal pollens, dust mites, animal allergens, and certain mold spores. Over the ensuing decades, laboratory investigations have provided objective evidence to demonstrate immunologic changes, including production of protective IgG antibody, suppression of IgE antibody, upregulation of regulatory T cells, and induction of a state of immune tolerance to the offending allergen(s). Tangential to this work were carefully designed clinical studies that defined allergen dose and duration of treatment, established the importance of preparing extracts with standardized allergens (or well-defined extracts) based on major protein moieties, and used allergen provocation models to demonstrate efficacy superior to placebo. In the United States, the use of subcutaneous immunotherapy extracts for AIT was grandfathered in by the Food and Drug Administration based on expert literature review. In contrast, sublingual tablet immunotherapy underwent formal clinical development programs (phase I-III clinical trials) that provided the necessary clinical evidence for safety and efficacy that led to regulatory agency approvals for the treatment of allergic rhinitis in properly characterized patients with allergy. The allergy specialist's treatment options currently include traditional subcutaneous AIT and specific sublingual tablets approved for grass, ragweed, house dust mites, trees belonging to the birch-homologous group, and Japanese cedar. Tangential to this are sublingual drops that are increasingly being used off-label (albeit not approved by the Food and Drug Administration) in the United States. This article will review the evidence-based literature supporting the use of these forms of AIT, as well as focus on several current controversies and gaps in our knowledge base that have relevance for the appropriate selection of patients for treatment with specific AIT., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Ocular allergy (OA) is a localized subset of allergy characterized by ocular surface itchiness, redness and inflammation. Inflammation and eye-rubbing, due to allergy-associated itch, are common in OA sufferers and may trigger changes to the ocular surface biochemistry. The primary aim of this study is to assess the differences in the human tear proteome between OA sufferers and Healthy Controls (HCs) across peak allergy season and off-peak season in Victoria, Australia., Methods: 19 participants (14 OA sufferers, 5 HCs) aged 18-45 were recruited for this study. Participants were grouped based on allergy symptom assessment questionnaire scoring. Proteins were extracted from human tear samples and were run on an Orbitrap Mass Spectrometer. Peaks were matched to a DIA library. Data was analyzed using the software MaxQuant, Perseus and IBM SPSS., Results: 1267 proteins were identified in tear samples of OA sufferers and HCs. 23 proteins were differentially expressed between peak allergy season OA suffers vs HCs, and 21 were differentially expressed in off-peak season. Decreased proteins in OA sufferers related to cell structure regulation, inflammatory regulation and antimicrobial regulation. In both seasons, OA sufferers were shown to have increased expression of proteins relating to inflammation, immune responses and cellular development., Conclusion: Tear protein identification showed dysregulation of proteins involved in inflammation, immunity and cellular structures. Proteins relating to cellular structure may suggest a possible link between OA-associated itch and the subsequent ocular surface damage via eye-rubbing, while inflammatory and immune protein changes highlight potential diagnostic and therapeutic biomarkers of OA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Aydin, Nie, Azizoglu, Chong, Gokhale and Suphioglu.)

We investigated the prophylactic and therapeutic effects of the oral administration of transgenic rice seeds expressing a hypoallergenic Bet v 1 derivative of allergic birch pollen conjunctivitis in mice. Transgenic rice seed depositing a chimeric molecule called TPC7 (tree pollen chimera 7) created by DNA shuffling of Bet v 1 family sequences from birch, alder and hazel in protein bodies of endosperm was generated. BALB/c mice were sensitized to birch pollen in alum and challenged with pollen in eyedrops. They were fed TPC7 transgenic or non-transgenic (control) rice seeds for 14 d before sensitization (prophylactic protocol) or 17 d after sensitization (therapeutic protocol). The clinical score and number of conjunctival eosinophils were significantly lower in TPC7-fed mice than in the control mice based on both the prophylactic and therapeutic protocols. Serum concentration of allergen-specific IgE did not differ between TPC7-fed and control groups in either protocol. Prophylactic administration of TPC7 downregulated the production of IL-4 and IFN-γ, whereas therapeutic administration of TPC7 upregulated the production of IFN-γ by allergen-stimulated splenocytes. Prophylactic or therapeutic oral administration of transgenic rice expressing TPC7 suppressed birch pollen-induced allergic conjunctivitis in mice. Feeding transgenic rice is a potentially effective approach as an allergen-specific immunotherapy for allergic conjunctivitis.

The aim of this study was to determine the effects of traffic-related particulate matter (PM) on allergic inflammation of ocular surfaces. BALB/c mice were sensitized with ovalbumin (OVA) and aluminum hydroxide via intraperitoneal injection. Two weeks later, mice were challenged with eye drops containing OVA concomitant with either traffic-related PM 2.5 or vehicle eye drops. Topical OVA challenges were administered following unilateral subconjunctival injection of magnetic-bead-sorted CD11c+ dendritic cells (DC). The following were assessed: (1) clinical signs, (2) infiltration of inflammatory cells into conjunctiva, (3) serum levels of OVA-specific IgE production, and (4) T-cell cytokine secretion with topical application of PM 2.5 , compared to saline vehicle. PM 2.5 was found to increase production of OVA-specific IgE in serum and Th2 immune response-related cytokines including interleukin (IL)-4, IL-17A, and IL-13 compared to vehicle control. It is of interest that PM 2.5 treatment also elevated the population of mature DCs in draining lymph nodes (LNs). Exposure with PM 2.5 was associated with a significant rise in conjunctival expression of IL-1β, IL-6, IL-17, and TNF. After subconjunctival injection of CD11c+DCs from PM 2.5 -treated allergic conjunctivitis (AC) mice into naïve mice, T cell responses and OVA-specific IgE were also enhanced. Data suggest that traffic-related PM 2.5 exacerbated allergic conjunctivitis as evidenced by increased infiltration of inflammatory cells into the conjunctiva and Th2 responses in the draining LNs associated with enhanced maturation of DCs. Our findings provide new insight into the hazardous potential of traffic-related PM 2.5 on allergic diseases, such as asthma or atopic dermatitis.

Purpose: To investigate whether crude house-dust-mite antigen exacerbates eosinophilic inflammation in the conjunctival tissues of an atopic keratoconjunctivitis mouse model in a dose-dependent manner., Materials and Methods: An atopic keratoconjunctivitis mouse model was established by percutaneous sensitization and crude house-dust-mite antigen application in NC/Nga mice. To assess the dose-dependent response, conjunctival specimens from groups that were administered high- (High-HDM) or low-dose house-dust-mite antigen (Low-HDM) following percutaneous sensitization and the control without house-dust-mite antigen administration (control group) were evaluated. Histological examination and immunofluorescence staining were performed to determine eosinophil density and the number of IL-13-positive cells. Polymerase chain reaction array was used to obtain adaptive and innate immunity-related factor profile, and quantitative polymerase chain reaction was used to determine Il13, Il17a, Ccl11, and Ccl24 expression. Atopic keratoconjunctivitis model mice injected with anti-IL-1α antibody (IL-1α group) or vehicle (vehicle group) to the upper and lower eyelids before atopic keratoconjunctivitis development were evaluated., Results: Eosinophil density in the conjunctiva increased with house-dust-mite antigen application in a dose-dependent manner. CD4, CXCL10, CCR6, C3, and IL-13 mRNA levels increased more than 5-fold in the conjunctiva of the High-HDM group animals compared to those in control animals. mRNA expression of Il13 and Ccl11 in the conjunctiva of the High-HDM group animals significantly increased compared with that in the Low-HDM and control group animals. Conversely, the eosinophil density and Il13 mRNA expression significantly decreased in the IL-1α group compared with those in the vehicle group., Conclusions: The house-dust-mite antigen increased eosinophilic infiltration and Il13 mRNA expression in the conjunctiva of an atopic keratoconjunctivitis mouse model in a dose-dependent manner. These inflammatory alterations were partially alleviated by eyelid injection of anti-IL-1α antibody. These findings indicate that IL-1α-induced IL-13 production constitutes a major exacerbating factor for house-dust-mite antigen-induced atopic keratoconjunctivitis.

Background: Allergen immunotherapy (AIT) is the only disease-modifying treatment in patients with seasonal allergic rhinoconjunctivitis (SAR). Its efficacy depends on the precise identification of the triggering allergen. However, diagnostics based on retrospective clinical history and sensitization to whole extracts (SWE) often leads to equivocal results., Objectives: To assess the usability and impact of a recently established algorithm for a clinical decision support system (@IT2020-CDSS) for SAR and its diagnostic steps [anamnesis, SWE (skin prick test or serum IgE), component resolved diagnosis, CRD, and real-time digital symptom recording, eDiary] on doctor's AIT prescription decisions., Methods: After educational training on the @IT2020-CDSS algorithm, 46 doctors (18 allergy specialists, AS, and 28 general practitioners, GP) expressed their hypothetical AIT prescription for 10 clinical index cases. Decisions were recorded repeatedly based on different steps of the algorithm. The usability and perceived impact of the algorithm were evaluated., Results: The combined use of CRD and an eDiary increased the hypothetical AIT prescriptions, both among AS and GP (p < .01). AIT prescription for pollen and Alternaria allergy based on anamnesis and SWE was heterogeneous but converged towards a consensus by integrating CRD and eDiary information. Doctors considered the algorithm useful and recognized its potential in enhancing traditional diagnostics., Conclusions and Clinical Implications: The implementation of CRD and eDiary in the @IT2020-CDSS algorithm improved consensus on AIT prescription for SAR among AS and GP. The potential usefulness of a CDSS for aetiological diagnosis of SAR and AIT prescription in real-world clinical practice deserves further investigation., (© 2021 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Allergen-specific immunotherapy (AIT) is the only means of altering the natural immunological course of allergic diseases and achieving long-term remission. Pharmacological measures are able to suppress the immune response and/or ameliorate the symptoms but there is a risk of relapse soon after these measures are withdrawn. Current AIT approaches depend on the administration of intact allergens, often comprising crude extracts of the allergen. We propose that the challenges arising from current approaches, including the risk of serious side-effects, burdensome duration of treatment, poor compliance and high cost, are overcome by application of peptides based on CD4 + T cell epitopes rather than whole allergens. Here we describe evolving approaches, summarize clinical trials involving peptide AIT in allergic rhinitis and asthma, discuss the putative mechanisms involved in their action, address gaps in evidence and propose future directions for research and clinical development., (© 2021 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Objectives: To compare the impact of different formulas on the occurrence of other atopic manifestations and the time of immune tolerance acquisition., Study Design: In a 36-month prospective cohort study, the occurrence of other atopic manifestations (eczema, urticaria, asthma, and rhinoconjunctivitis) and the time of immune tolerance acquisition were comparatively evaluated in immunoglobulin E-mediated children with cow's milk allergy (CMA) treated with extensively hydrolyzed casein formula containing the probiotic L. rhamnosus GG (EHCF + LGG), rice hydrolyzed formula, soy formula, extensively hydrolyzed whey formula (EHWF), or amino acid-based formula., Results: In total, 365 subjects were enrolled into the study, 73 per formula cohort. The incidence of atopic manifestations was 0.22 (Bonferroni-corrected 95% CI 0.09-0.34) in the EHCF + LGG cohort; 0.52 (0.37-0.67) in the rice hydrolyzed formula cohort; 0.58 (0.43-0.72) in the soy formula cohort; 0.51 (0.36-0.66) in the EHWF cohort; and 0.77 (0.64-0.89) in the amino acid-based formula cohort. The incidence of atopic manifestations in the rice hydrolyzed formula, soy formula, EHWF, and amino acid-based formula cohorts vs the EHCF + LGG cohort was always greater than the prespecified absolute difference of 0.25 at an alpha-level of 0.0125, with corresponding risk ratios of 2.37 (1.46-3.86, P < .001) for rice hydrolyzed formula vs EHCF + LGG; 2.62 (1.63-4.22, P < .001) for soy formula vs EHCF + LGG; 2.31 (1.42-3.77, P < .001) for EHWF vs EHCF + LGG; and 3.50 (2.23-5.49, P < .001) for amino acid-based formula vs EHCF + LGG. The 36-month immune tolerance acquisition rate was greater in the EHCF + LGG cohort., Conclusions: The use of EHCF + LGG for CMA treatment is associated with lower incidence of atopic manifestations and greater rate of immune tolerance acquisition., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The purpose of this article is to review the pathophysiologic mechanisms, differential diagnosis, evaluation, and treatment of the various manifestations of ocular allergy, with an especial focus on immunoglobulin E (IgE)-mediated disease., Data Sources: A PubMed search was performed to include articles, using the search terms ocular allergy and allergic conjunctivitis., Study Selections: Recent and relevant human studies in the English language pertaining to our topic of study were selected. Animal studies pertaining to pathophysiology of ocular allergy were also reviewed. We focused on clinical trials, practice guidelines, reviews, and systematic reviews. In addition, case reports were reviewed if they described rare clinical presentations, disease mechanisms, or novel therapies., Results: Ocular allergy encompasses both IgE- and non-IgE-mediated disease, and the clinical severity may range from mild to sight-threatening inflammation. A comprehensive treatment regimen including education, lifestyle measures, topical therapies, and even systemic interventions may be necessary for the effective management of ocular allergies, tailored according to symptom severity., Conclusion: Ocular allergy is frequently encountered by allergists and eye-care specialists, and despite progressively increasing incidence, it often remains underdiagnosed and, hence, untreated., (Copyright © 2021 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Allergic rhinoconjunctivitis is a global health problem. Different allergen immunotherapy regimes are marketed but have low adherence because they are expensive, complex, and time-consuming. New allergen immunotherapy forms are needed., Objective: In a 3-year follow-up double-blind randomized placebo-controlled trial, we aimed to investigate the effect of intralymphatic allergen immunotherapy (ILIT)., Methods: Patients with grass pollen rhinoconjunctivitis were treated with 3 ILIT injections and an ILIT booster 1 year later, 3 ILIT injections and a placebo booster, or 3 placebo injections and a placebo booster. Primary outcome was improvement in a combined symptom and medication score (cSMS). A novel evaluation tool with a linear regression model of cSMS and grass pollen counts was developed. Secondary outcomes were changes in grass specific immunoglobulins and skin and nasal provocation tests to grass pollen., Results: A total of 36 patients were included. Log 10 -transformed cSMS was reduced by 0.30 (95% CI, 0.11-0.49; P = .002), equaling 48.5% (95% CI, 24.5%-62%), in the entire 3-year follow-up period, significant only in the first follow-up season but not in the second and third seasons. The regression model showed a 37% (P < .001) reduction in cSMS. The booster injection 1 year later had no additional effect. Secondary, repeated measures of IgE and IgG 4 to grass showed significant between-group difference and within-group change in the ILIT groups. No change in provocation test results was found., Conclusions: ILIT gives a substantial reduction in grass pollen allergy symptoms and use of rescue medication, significant in the first season after treatment. A booster injection had no additional effect., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: As the number of allergic sensitizations increases the severity of allergic respiratory diseases worsens. Multiple monoallergen immunotherapy can be accompanied by poor treatment adherence and high costs, single multiallergen immunotherapy needs to prove efficacy whilst maintaining a good safety profile., Methods: Observational, retrospective, multicenter study using a 2-pollen single undiluted multiallergen subcutaneous immunotherapy (SCIT) in routine clinical practice in Spain. Patients with rhinoconjunctivitis, with/without controlled asthma, sensitized to grass, olive, Parietaria, Cupressus, plane tree and/or Salsola pollen were included. Primary and secondary clinical efficacy endpoints were quality of life (mini Rhinitis Quality of Life Questionnaire (miniRQLQ)) and visual analogue scale (VAS) respectively. All adverse events were documented., Results: Ten centers included 97 patients, median age 32 years. SCIT treatment included combinations of grass mix with olive, Parietaria, Cupressus, plane tree or Salsola or olive with Parietaria, Cupressus or Salsola. The mean duration of SCIT was 1.8 years with a high treatment adherence (73%). Significant improvement in quality of life, nasal and ocular symptoms, activity limitations and practical problems (p< 0.0001) and other symptoms (p= 0.024) was observed. Most patients did not develop asthma-like symptoms and a significant improvement of all allergic symptom severity was perceived. VAS showed a significant improvement in rhinoconjunctivitis and asthma by patients and physicians. Twenty-nine patients experienced adverse reactions, 25 had local and 6 had systemic reactions., Conclusions: Single undiluted multiallergen SCIT treatment of two different pollens is efficacious and safe in both children and adults, showing that it is a suitable option for the treatment of polyallergic patients., (© 2021 S. Karger AG, Basel.)

Mouse models of allergic conjunctivitis mimic various aspects of human allergic conjunctivitis. They are useful as acute models of allergic conjunctivitis to study immunological aspects of this condition. In this chapter, we will describe ragweed-pollen-induced experimental allergic conjunctivitis (mostly driven by adaptive immunity), and papain-soaked contact lens-induced experimental allergic conjunctivitis (mostly driven by innate immunity). Giemsa staining of histological sections is used for quantification of the number of infiltrating eosinophils, which is useful to evaluate the severity of the allergic inflammation. Immunohistochemical staining and quantitative PCR are used to clarify spatiotemporal expression of proinflammatory molecules in the conjunctival tissue. Flow cytometric analysis of conjunctival tissue is used for the detection of innate lymphoid cell type 2 (ILC2) in the ocular surface tissues.

Purpose of Review: The purpose of this article is to provide an overview of the literature pertaining to the use of allergen immunotherapy for treatment of allergic conjunctivitis with an emphasis on recent developments., Recent Findings: Both subcutaneous (SCIT) and sublingual (SLIT) immunotherapy continue to show efficacy in treating allergic conjunctival disease, subcutaneous more than sublingual. Adverse effects of sublingual therapy continue to be reported since the FDA's approval of SLIT tablets in 2014. Initial SLIT studies reported high rates of adherence, while real use reports identify rates of nonadherence/discontinuation ranging between 50 and 80%. Studies in polyallergic patients evaluating the efficacy of SLIT combination therapy report encouraging results., Summary: Both SCIT and SLIT offers improvement in allergic conjunctival symptom scores and decrease medication utilization. Although SCIT has a higher likelihood of systemic reaction, SLIT has a very high rate of mild-to-moderate adverse events - especially in the first month. Cost-benefit analyses tend to favor SCIT (greater efficacy and less impacted by discontinuation rates).

Background: In allergology, the intradermal approach is generally used to establish an aetiological diagnosis, with limited experience in specific allergen immunotherapy., Objective: To evaluate the efficacy and safety of immunotherapy with an allergen extract of glutaraldehyde-polymerized Phleum pratense, administered intradermally, in patients with rhinoconjunctivitis sensitized to grass pollen., Methods: Multicentre, randomized, double-blind, placebo-controlled clinical trial in patients from 12 to 65 years of age with rhinitis or rhinoconjunctivitis, with or without asthma, due to grass pollen allergy. Patients were divided into three groups and received a total of six doses in a weekly interval, of either placebo; 0.03 or 0.06 μg of protein per dose of P pratense allergoid. The primary objective was to evaluate the combined symptoms and medication consumption score (CSMS). The secondary objectives were symptoms and medication, tolerance to the conjunctival provocation test, specific IgE and IgG4 antibodies and the safety profile according to the WAO scale., Results: The dose of 0.06 μg of protein proved to be effective versus the placebo by significantly reducing CSMS and increasing tolerance to the allergenic extract in the conjunctival provocation test, after the first pollen season. This group showed a significant reduction in specific IgE after the second pollen season relative to the baseline. There were no variations in IgG4 levels. Only one grade 2 systemic reaction was recorded., Conclusion & Clinical Relevance: Intradermal immunotherapy with P pratense allergoid has been shown to be effective and safe, reducing CSMS, increasing tolerance to the conjunctival provocation test and reducing IgE levels., (© 2020 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Background: Ocular allergies affect an estimated 40% of the population, 98% of which are because of allergic conjunctivitis and includes tear film dysfunction. With the current advent of both repurposed drugs for ocular allergies, as well as novel drugs, lubricants and methods of administration, there is a need to update new treatments to optimize the care of ocular allergy patients. Methods: An overview of mediators, clinical characteristics and management is provided in a summary format. Results: Lubricants (best when refrigerated provide immediate relief that is short lived (several minutes) due to its dilutional effect on mediators and pollen in the tear film. Immediate and longer-term benefit occurs from different topical and oral medications - primarily histamine receptor agonists. Conclusion: The newest prescription topical ophthalmic histamine H1 receptor antagonist (an inverse agonist) to be approved by the U.S. Food and Drug Administration in the past 10 years (U.S. NDA approved May 30, 2017) is cetirizine ophthalmic solution for the treatment of ocular itching with allergic conjunctivitis in adults and in children more than 2 years old.

Allergic conjunctivitis is one the most common global diseases and affects many people worldwide. It has been reported that 15% to 20% of the total population in Japan suffers from allergic conjunctival disease. Although TH2 cytokines suchs as interleukin (IL)-4, IL-5, and IL-13 have long been known as causes of allergic conjunctivitis, new cytokines involved in allergic diseases have been identified since 2000. The discovery of type 2 immune response-initiating cytokines, such as IL-25, IL-33, and thymic stromal lymphopoietin, and type 2 innate lymphoid cells has suggested that allergic diseases can arise from not only T cells but also barrier function disruption. In this article, we summarize the results of experiments in mouse models of ragweed-induced experimental allergic conjunctivitis and papain-soaked contact lens-induced conjunctivitis.

Background: Allergic respiratory diseases such as asthma and allergic rhinitis have increased considerably in the last decades., Objective: The present study estimates prevalence trends of asthma, allergic rhinitis and pollinosis in the population of a city of Southern Brazil, without restriction of age, from 2011 to 2018, using the ISAAC standardized questionnaire., Methods: Data was collected from March to June of 2011 and during the same months in 2018, in order to verify trends in the prevalence of these allergic conditions. The total sample consisted of 3132 individuals of both sexes living in the municipality of Santo Ângelo, in the state of Rio Grande do Sul, Brazil., Results: No differences were observed in the prevalence of asthma diagnosis (15.1% in 2011 and 13.8% in 2018), however the prevalence of current wheeze was significantly reduced from 24.7% in 2011 to 21.2% in 2018 (p<0.05). Regarding allergic conditions in 2011 and in 2018, a significant reduction was observed (p<0.001) in reported current rhinitis (63.3% vs. 50.5%), rhinoconjunctivitis (48.9% vs. 38.8%), hay fever (52.0% vs. 43.3%), and pollinosis (29.0% vs 17.0%). Moreover, we observed an inverse relation between age and rhinoconjunctivitis and hay fever, and all symptoms were more frequent in females. Rhinoconjunctivitis and hay fever, as well as current rhinitis and pollinosis were highly prevalent among 30-39 years-old individuals, whereas current wheeze affected mainly the age group 10-19 years-old., Conclusion: While the prevalence of asthma remained similar after seven years, allergic rhinitis and pollinosis declined between 2011 and 2018., (Copyright © 2020 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.)

This study was to explore a novel IL-33/ST2/IL-9/IL-9R signaling pathway that disrupts ocular surface barrier and amplifies allergic inflammation. Two murine models of experimental allergic conjunctivitis (EAC) and IL-9 topical challenge in wild type Balb/c and ST2 -/- mice, and two culture models of primarily human corneal epithelial cells (HCECs) and mouse CD4 + T cells were performed. Clinical manifestations, Oregon-Green Dextran (OGD) staining, the apical junction complexes (AJCs), IL-33/ST2 and IL-9/IL-9R signaling molecules were evaluated in ocular surface and its draining cervical lymph nodes (CLNs) by RT-qPCR, immunostaining and ELISA. The typical allergic signs, enhanced OGD staining intensity, disrupted morphology of AJCs, including ZO-1, claudin 1, occludin, and E-cadherin, and the stimulated signaling of IL-33/ST2 and IL-9/IL-9R were observed in ocular mucosa and draining CLNs in EAC-Balb/c mice, but significantly reduced or eliminated in EAC-ST2 -/- mice. Topical challenge of IL-9 resulted in the obvious OGD staining and disrupted ocular surface AJCs in Balb/c mice and in HCECs in vitro. IL-9 production was found to be stimulated by IL-33 in CD4 + cells from Balb/c mice in vitro. Our findings uncovered a novel phenomenon and mechanism by which ocular surface barrier integrity is disrupted in allergic conjunctivitis by IL-33/ST2/IL-9/IL-9R signaling pathway, which may amplify the allergic inflammation.

Ocular allergic diseases are frequently seen in ophthalmological clinical practice. Immunological damage is mediated by a local Th2 inflammatory microenvironment, accompanied by changes in circulating cell subsets, with more effector cells and fewer T regulatory cells (Tregs). This study aimed to evaluate the involvement of toll-like receptor 4 (TLR4) and α-melanocyte stimulating hormone (α-MSH) in the immune regulation associated with perennial allergic conjunctivitis (PAC). We performed an Ag-specific stimulation during 72 h of culturing with or without lipopolysaccharide (LPS) or α-MSH in peripheral blood mononuclear cells (PBMC), analyzing the cell subsets and cytokines induced by the stimuli. We also determined α-MSH in tear samples from healthy donors (HD) or PAC patients. Our findings demonstrate an immunological dysregulation characterized by an increased frequency of CD4+TLR4+ in the PBMC of patients with PAC, compared to HD. Most of these CD4+TLR4+ cells were also CD25+, and when α-MSH was added to the culture, the percentage of CD4+CD25+FoxP3+ increased significantly, while the percentage of CD69+ cells and cytokines IL-4 and IL-6 were significantly decreased. In tears, we found an increased concentration of α-MSH in PAC patients, compared with HD. These findings indicate a novel mechanism involved in controlling ocular allergic diseases, in which α-MSH diminishes the concentration of IL-6 and IL-4, restoring the frequency of Tregs and down-regulating CD4 activation. Moreover, we demonstrated the involvement of CD4+TLR4+ cells as an effector cell subset in ocular allergy.

Purpose of Review: The rising global burden of allergic diseases, particularly in the pediatric population, is of serious concern. Ocular allergy is one of the most common ocular pathologies met in clinical practice. A large proportion of children and adolescents suffer from allergic eye diseases (AEDs), which affect their quality of life. The available treatments and surgical modalities have their limitations and side effects. Therefore, the development of novel and alternate strategies is the need of the hour and requires a timely review of currently available knowledge., Recent Findings: The current review covers the incidence and prevalence of AEDs, factors influencing occurrence and severity of AED (age, sex, socioeconomic status etc.), underlying mechanisms, role of allergy testing and immunotherapy in children, development of diagnostic markers and novel therapies including cells and molecules., Summary: Understanding the demographics, clinical patterns and risk factors of AED can help formulate appropriate preventive and therapeutic strategies for the effective management of this common cause of ocular morbidity. The future therapeutics for AED seems to rely primarily on cells (mesenchymal stem cells, Tregs, mast cells), cell products, molecules with immunosuppressive potential and immunotherapy.

Allergic conjunctival diseases (ACDs) are inflammatory diseases of the conjunctiva and cornea caused predominantly by the IgE-mediated immediate hypersensitivity response. Allergic conjunctival diseases include allergic conjunctivitis, vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), and giant papillary conjunctivitis. In clinical practice of ACDs, an ocular allergy test using biomarker measurement is a crucial examination technique for diagnosing, evaluating severity, and determining the efficacy of medical treatment. The ocular allergy test includes the tear test for evaluating the concentration of biomarkers in tears and an ocular surface test for assessing the expression levels of messenger ribonucleic acid (mRNA) biomarkers on the ocular surface. The clinical usefulness of several biomarkers has been demonstrated in patients with ACDs; specifically, eosinophil cationic protein and eotaxin-2 as eosinophilic inflammation biomarkers; interleukin-4 and thymus and activation regulated chemokine (CCL17/TARC) as Th2 inflammation biomarkers; eotaxin, tumor necrosis factor-alpha and soluble IL-6 receptor as giant papillae biomarkers; and osteopontin and periostin as allergic inflammation and remodeling biomarkers. Furthermore, the ocular allergy test, quantitative evaluation methods using biomarkers have allowed for better understanding of the immunological and pathophysiological mechanisms of ACDs. Therefore, the search for a biomarker is important to make an ocular allergy test useful. In previous ocular allergy tests, the biomarkers for allergic inflammation in patients with chronic ACDs including VKC and AKC were substantial. However, the selection of biomarkers associated with the early phase reaction of immediate hypersensitivity and innate immunity responses needs to be addressed in future investigations., (Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Introduction: Atopic keratoconjunctivitis (AKC) is a form of allergic eye disease that can have sight threating implications. Prevalence is underestimated due to scarce published data and treatment is expanding as a result of limitations of current strategies. This article aims to provide an up-to-date overview of AKC and summarize current and upcoming management., Areas Covered: The authors provide history, immunopathogenesis, and summary of the clinical manifestations of AKC as well as presenting a review of the evidence in relation to treatment options including mast cell stabilizers, antihistamines, corticosteroids, and immunomodulatory drugs based on clinical trials. Future trends, drug targets, and novel delivery drug systems are also highlighted in this review., Expert Opinion: Previously established treatment strategies of AKC had relied on corticosteroids, but the side effects of long-term therapy resulted in the expansion into the use of immunomodulatory drugs such as tacrolimus and ciclosporin. However, these too provide limited success due to the suboptimal structural properties of the current molecules. The ideal molecule should generate maximum permeability across the multi-layered structure of the cornea, be able to be formulated into eye drops for ease of application with minimal dosing and for maximal clinical effect.

Purpose of Review: This article reviews the ocular findings in patients with a myriad of autoimmune syndromes. This review will provide guidance and heighten awareness for the allergist or eye care provider to pay heed to the manifestations and treatments of autoimmune syndromes., Recent Findings: Autoimmune syndromes can present with varied manifestations on the ocular surface known to potentially cause significant visual morbidity. In particular, sterile corneal ulcers are the most devastating and common finding in uncontrolled autoimmune disease. Ophthalmic manifestations of autoimmune syndromes have been reported individually; however, herein we present a comprehensive review of typical and atypical syndromes that may present with sterile corneal ulceration., Summary: Autoimmune inflammatory syndromes are known to be associated with ocular surface inflammatory processes ranging from bothersome dry eye syndromes to vision-threatening sterile corneal ulceration. It is important to pay heed to the clinical presentation of common and uncommon presentations of the syndromes in the eye. We propose best practice for management of ocular surface disease in these clinical entities.

Purpose of Review: Chemokines are a large group of low molecular weight cytokines that attract and activate leukocytes throughout the body and therefore have a key role in the framework of late-phase allergic responses. The purpose of this article is to provide an overview of the main chemokines involved in allergic conjunctivitis, their primary functions and their physiological roles, and therapies targeted at chemokines and their receptors for ocular allergic diseases., Recent Findings: In recent years, there have been considerable advances in the understanding of ocular pathophysiology of ocular surface inflammatory diseases including both allergic eye diseases and dry eye syndrome. Several therapies being developed for dry eye inflammation are recognized as possible therapies for ocular allergic diseases as there are often common chemokines involved in both disease spectra., Summary: Chemokines represent an integral part of the late-phase cascade of ocular allergic inflammation. A deep understanding of specific chemokines and their interactions will help in targeting therapies to effectively manage ocular clinical findings and symptoms of allergic eye disease.

Purpose of Review: Vernal keratoconjunctivitis (VKC) is a rare chronic self-limiting allergic inflammatory disease of the ocular surface mostly affecting young boys in their first decade of life. In the last few years a new clinical entity of VKC has been described: adult VKC. Two variants have been identified according to clinical onset: early (childhood VKC persisting beyond puberty) and late onset (arising de novo in adults) adult VKC. Several epidemiologic studies on VKC have been published from single tertiary centers but while the age distribution of VKC patients does show a small percentage of adults with the disease, detailed analysis on this small subset of adult VKC cases is lacking. In this review we describe pathogenesis, clinical features, diagnostic alternatives, and therapeutic alternatives of this highly invalidating disease., Recent Findings: Adult variants of VKC have same clinical manifestations of classic form, but show higher inflammatory response and increased risk of chronic fibrotic sequelae., Summary: Adult VKC research could provide insights on the impact of sex hormones in the pathogenesis of allergic diseases and on the mechanisms of inflammation and fibrosis, which cause potentially vision threatening sequelae. The present review will highlight the recent developments in our understanding of this uncommon entity.

Summary: Objectives. To evaluate the tolerability and efficacy of Olea europaea subcutaneous immunotherapy (SCIT) on patients with rhinoconjunctivitis. Methods. In this open clinical trial patients were assigned to an abbreviated build-up scheme. The outcomes were: number, percentage, and severity of adverse reactions. Secondary outcomes included: changes in immunoglobulin titers and changes in dose-response skin prick tests. Results. Only 8 systemic reactions were registered, which represented 7/47 (14.9%) of patients and 8/429 (1.9%) of administered doses. Regarding immunological parameters the significant increases of sIgG and sIgG4 evidenced the changes in the patient immune system. Cutaneous reactivity decreased significantly. Conclusions. Olea europaea SCIT (Allergovac® depot ROXALL Medicina España S.A.) showed a good safety and tolerability profile. Immunological changes with induction of blocking IgG and decreases in cutaneous reactivity were detected in the patients.

Purpose of Review: Ocular allergies affect an estimated 40% of the population, 98% of which are because of allergic conjunctivitis. With the current advent of both repurposed drugs for ocular allergies, as well as novel drugs and methods of administration, there is a need for an updated review of current available medications. A clear characterization of each treatment will ultimately allow treating physicians to restore patients' quality of life and decrease burden of disease., Recent Findings: Currently, there are a number of reformulated antihistamines, with cetrizine being the most recent ophthalmic solution available. Nevertheless, there is ongoing research in the field of immunotherapy, steroids, flavonoids, cannabis, and drug-delivery systems., Summary: Although dual-activity agents remain the keystone for treatment, newer drugs and drug-delivery systems offer other novel directions for delivering appropriate relief with minimal adverse effects.

Introduction: Allergic rhino-conjunctivitis is a highly prevalent condition. In moderate to severe cases, allergen immunotherapy (AIT) is a cost-effective therapeutic option. Previous data have reported a large difference in treatment compliance of subcutaneously (SCIT) and sublingually (SLIT) administered AIT., Methods: By use of the unique civil registration number assigned to all Danish citizens and the Danish National Health Service Prescription Database, compliance rates of all patients prescribed with grass pollen AIT from January 1998 until December 2016 were analysed annually during the three-year treatment period., Results: The male/female ratio was close to 1:1 in SCIT, while SLIT was more frequently used by men. A large proportion of users was children or adolescents (32% and 45%, SCIT and SLIT, respectively). Compliance of both subcutaneous and sublingual treatment gradually fell each year; compliance in year 3 was 57% and 53% for subcutaneous and sublingual treatment, respectively. Compliance of grass pollen sublingual treatment was also analysed each year after registration on the Danish market. Compliance significantly increased following the introduction and stabilised on a relatively high level., Conclusion: Based on previous studies, we hypothesised that AIT compliance would be low, especially in SLIT. However, in Denmark, compliance in SCIT and SLIT was almost similar, and the majority of patients completed the three-year treatment period with a compliance in the last quintile., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Canine allergic conjunctivitis (cAC) is described as the most frequent ocular manifestation associated with canine atopic dermatitis (cAD)., Objectives: Clinical and immunological characterization of cAD through IL-6, TNF-α and IL-12 mRNA expression quantification in canine conjunctivae., Procedures: Twenty client-owned dogs with both cAC and cAD and twenty-one healthy controls were enrolled and clinician assessed CADESI-04 and grade of ocular signs were calculated. Conjunctival biopsies were performed on all animals and relative quantification of the interleukins mRNA expression performed by qRT-PCR. The correlation between cytokine gene expression and cAC score was evaluated, as well as CADESI-04 values., Results: The qRT-PCR showed a significant gene upregulation of respectively 291.48 (p = 1.306e-09) and 4.85 (p = .00033) folds on IL-6 and IL-12 in dogs with allergic conjunctivitis compared to the control group. Regarding the average expression of TNF-α there were no statistical significant differences between both groups (p = .18). Higher cAC scores were associated with enhanced gene expression of TNF-α and IL-12. No correlation was found between the cytokine gene expression levels and the CADESI-04 values., Conclusion: An increase of IL6 and IL12 in cAC was found in the studied population. These two cytokines may be potential immunotherapy targets cAC classification., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Atopic dermatitis (AD) is a chronic relapsing eczematous dermatitis typically affecting young patients in a percentage from 15 to 20%; although it typically affects young people and adults, recent papers highlighted the emerging of the disease in the elderly population., Methods: The aim of the study was to identify the clinical criteria and allergic sensitization that may be able to support physicians and dermatologists in making a correct diagnosis of AD in the elderly. The second aim of this study was to investigate the incidence, the main features, the gender prevalence, the immunological profile, and comorbidities characterizing patients older than 65 years affected by AD., Results: Based on clinical and serological patterns, different phenotypes of AD were identified: generalized AD (55%) characterized by eczematous lesions involving typical areas of the body or prurigo nodularis-like AD; chronic eczematous hand dermatitis (23%); face and neck involvement (9%); and nummular eczema (13%). Skin prick tests revealed a positivity for aeroallergens in 49.6% of patients, most of them being polysensitized (55%). Additionally, food skin prick tests were positive in 25% of patients. Most of the patients reported comorbidities, particularly IgE-mediated diseases, such as seasonal rhino-conjunctivitis, asthma, and chronic obstructive pulmonary disease. Gastrointestinal symptoms such as meteorism, dyspepsia, cramps/abdominal pain, and diarrhea/constipation, were observed in 35% of patients consequent to food allergy., Conclusion: In our study, we suggest clinical and serological criteria that may be able to guide in the diagnosis of AD in Caucasian elderly, and to design an appropriate treatment according to the current standard protocol., (© 2020 The International Society of Dermatology.)

Introduction: Atopic dermatitis (AD) is a chronic inflammatory skin disease, and AD patients are commonly sensitized to house dust mite (HDM). Of the several treatment options available, allergen-specific immunotherapy (AIT) has been recognized as an effective treatment modality that is directed toward the immunoglobulin E (IgE)-mediated nature of AD, and subcutaneous administration using HDM is most commonly used for AIT in AD. For patients sensitized to animal (dog or cat) dander, the treatment may not be easy, especially when avoiding the allergen is not possible., Methods: This study enrolled patients with AD who were sensitized to cat and/or dog dander and underwent AIT (n = 19). Patients' medical information was obtained, including past treatment history, treatment duration of AIT, and the progress of treatment. Also, the specific IgE levels and IgG4 levels were measured before and after AIT., Results: A total of 19 patients with AD underwent AIT using cat and/or dog dander. The patients consisted of 4 males and 15 females with an average age of 31.74 ± 9.71. Only two patients had AD only, and the other 17 patients had one or more concomitant allergic diseases, such as allergic rhinitis, allergic asthma, or allergic conjunctivitis. Seven patients were not sensitized to HDMs and only sensitized to cat and/or dog dander. The duration of AIT ranged from 2 to 58 months. The symptoms of 17 patients were well-controlled, requiring only topical treatment and/or oral antihistamines. One patient required systemic cyclosporine, but only of low dose (25 mg/day). The specific IgE levels were decreased (P = .005) and IgG4 levels showed the tendency of increasing after AIT. No adverse events were observed in these patients., Conclusion: Although a larger number of patients for a longer follow-up period are needed to precisely assess the treatment efficacy, AIT using cat and/or dog dander may be an effective treatment option for AD patients, especially for severe AD patients with other respiratory allergic comorbidities who cannot completely avoid the exposure to animal dander., (© 2020 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Eosinophils are a major cause of tissue injury in allergic conjunctivitis. The biological nature of eosinophils in the conjunctiva and the mechanisms that control eosinophils' responses in allergic conjunctivitis are currently not completely understood. This study reports that conjunctival eosinophils comprise two populations-Siglec-F int and Siglec-F hi -in different life stages. Siglec-F int eosinophils partly expressed CD34 and were in the immature (or steady) state. Siglec-F hi eosinophils did not express CD34, sharply increased in number after short ragweed (SRW) pollen challenge, and were in the mature (or activated) state. Moreover, chemical sympathectomy by 6-hydroxydopamine reduced the recruitment and activation of eosinophils, whereas the activation of the sympathetic nerve system (SNS) with restraint stress accelerated the recruitment and activation of eosinophils in SRW-induced conjunctivitis. It was also found that two eosinophil populations expressed alpha-1a-adrenergic receptors (α1a-ARs); in SRW-induced conjunctivitis, treatment with an α1a-AR antagonist decreased eosinophil responses, whereas treatment with an α1a-AR agonist aggravated eosinophil responses. Thus, eosinophil responses in conjunctivitis are regulated by the SNS via α1a-AR signaling. SNS inputs or α1a-AR function may be potential targets for the treatment of allergic conjunctivitis., (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Introduction: Existing evidence on the relationship between childhood lower respiratory tract infections (LRTI) and the subsequent atopy development is controversial. We aimed to investigate an association between viral LRTI at <5 years and the development of atopy at > 2 years., Methods: We conducted a search at Embase, Pubmed, Web of Science, and Global Index Medicus. We collected data from the included articles. We estimated the odds ratio and the 95% confidence intervals with a random effect model. We determined factors associated with atopy development after childhood LRTI using univariate and multivariate meta-regression analyses. We recorded this systematic review at PROSPERO with the number CRD42018116955., Results: We included 24 studies. There was no relationship between viral LRTI at <5 years and skin prick test-diagnosed-atopy (OR = 1.2, [95% CI = 0.7-2.0]), unknown diagnosed-atopy (OR = 0.7, [95% CI = 0.4-1.3]), atopic dermatitis (OR = 1.2, [95% CI = 0.9-1.6]), hyperreactivity to pollen (OR = 0.8, [95% CI = 0.3-2.7]), food (OR = 0.8, [95% CI = 0.3-2.5]), or house dust mite (OR = 1.1, [95% CI = 0.6-2.2]). Although not confirmed in all studies with a symmetric distribution of the 23 confounding factors investigated, the overall analyses showed that there was a relationship between childhood viral LRTI at < 5 years and serum test diagnosed-atopy (OR = 2.0, [95% CI = 1.0-4.1]), allergic rhinoconjunctivitis (OR = 1.7, [95% CI = 1.1-2.9]), hyperreactivity diagnosed by serum tests with food (OR = 5.3, [1.7-16.7]) or inhaled allergens (OR = 4.2, [95% CI = 2.1-8.5]), or furred animals (OR = 0.6, [95% CI = 0.5-0.9])., Conclusion: These results suggest that there is no association between viral LRTI at < 5 years and the majority of categories of atopy studied during this work. These results, however, are not confirmed for the remaining categories of atopy and more particularly those diagnosed by serum tests. There is a real need to develop more accurate atopy diagnostic tools., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Thymic stromal lymphopoietin (TSLP) is a pro-allergic cytokine that initiates allergic inflammatory reaction between epithelial and dendritic cells (DCs). miR-19b was reported to suppress TSLP expression. The present study aimed to examine miR-19b expression, regulation, and function in allergic conjunctivitis (AC)., Methods: A murine model of experimental AC was induced in BALB/c mice by short ragweed pollen. The serum, eye balls, conjunctiva, and cervical lymph nodes (CLN) were used for the study. Gene expression was determined by RT-PCR, whereas protein production and activation were evaluated by immunostaining, ELISA, and Western blotting., Results: In the murine AC model, miR-19b was aberrantly downregulated, whereas the levels of TSLP and p-STAT3, as well as the number of CD11c+ pSTAT3+ DCs were increased. Moreover, Th2 inflammatory cytokine expression was significantly increased. These severe phenotypes could be counteracted by either applying exogenous miR-19b mimic microRNAs or the JAK/STAT inhibitor CYT387. Moreover, overexpression of miR-19b repressed p-STAT3 expression and the number of CD11c+ cells in AC eye and CLN tissues., Conclusions: These findings suggested that miR-19b reduced ocular surface inflammation by inhibiting Stat3 signaling via TSLP downregulation in a murine AC model. Moreover, the present study further demonstrated the clinical potential of applying miR-19b and anti-JAK/STAT therapies in the treatment of AC.

Background: Recent studies have proposed that clinical and immunological differences exist between mono- and poly-sensitized subjects with allergic diseases, and poly-sensitization was related to multimorbidity of allergic diseases among children and adolescents., Objective: We compared the clinical characteristics and multimorbidity of allergic diseases between adult rhinitis patients mono- and poly-sensitized to common aeroallergens using a retrospective cross-sectional study for tertiary care subjects., Methods: The medical records of 1,615 patients who were clinically diagnosed with rhinitis by an otolaryngologist and evaluated with skin prick tests were reviewed. The severity of the rhinitis symptoms, comorbidities (asthma, conjunctivitis, and eczema), family history of allergic diseases, and the results of skin prick tests were evaluated., Results: There were 392 patients with mono-sensitized rhinitis (mono-sR), 325 with poly-sensitized rhinitis (poly-sR), and 898 with non-sensitized rhinitis (non-sR). Comorbid conjunctivitis and eczema were most common in poly-sR, followed by mono-sR, and least common in non-sR patients. The age at onset of rhinitis was clearly different between adult patients with non-sR and mono-/poly-sR, but not between patients with mono-sR and poly-sR. However, the age at onset of rhinitis was much younger in non-sR and mono-sR patients with conjunctivitis or eczema than those without such comorbidities., Conclusion: Thefrequency of comorbid conjunctivitis and eczema in adult rhinitis patients differed by a quantitative trait of immunoglobulin E sensitization. Depending on the multimorbidity of allergic diseases, onset age of rhinitis seems to be different in adult rhinitis patients., (© 2020 S. Karger AG, Basel.)

Only few data on safety during high-dose, accelerated escalation schedules during subcutaneous allergen immunotherapy (AIT) are available. The aim of this study was to assess the safety and tolerability of an accelerated dose escalation schedule of AIT in adult patients with moderate to severe seasonal rhinoconjunctivitis in a multicenter, open-label, randomized phase II trial. The dose escalation scheme for patients in Group I (1 strength) included 3 injections with 1 strength, B (10,000 TU/mL), whereas the dose escalation scheme for Group II (standard) included 7 injections with 2 strengths, A (1,000 TU/mL) and B (10,000 TU/mL), of an aluminum hydroxide-adsorbed allergoid grass pollen preparation. Overall, 72 of 87 randomized patients (83.7%) reported at least 1 treatment-emergent adverse event (TEAE; 82.2 [Group I] vs. 85.4% [Group II]); 58.8% of all reported TEAEs were assessed as being related to AIT (60.0 vs. 48.8%). The most frequently reported AIT-related TEAEs were swelling (46.7 vs. 34.1%), erythema (28.9 vs. 36.6%), and pruritus (31.1 vs. 17.1%) at the site of the injection. Systemic allergic reactions occurred in 5 (5.8%) patients overall, with more being reported in the 1-strength group (4 [8.9%] vs. 1 [2.4%]). All systemic allergic reactions were classified as World Allergy Organization (WAO) Grade 1 or Grade 2 reactions. Accelerated high-dose escalation with an aluminum hydroxide-adsorbed grass pollen allergoid can be initiated with a safety and tolerability profile comparable to the standard dose escalation schedule in patients with allergic rhinitis with or without asthma., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Ambient air pollution is a well-recognized risk for various diseases including asthma and heart diseases. However, it remains unclear whether air pollution may also be a risk of ocular allergic diseases. Using a web-based, nation-wide, cross-sectional study design, we examined whether the level of ambient air pollution is significantly associated with the prevalence of ocular allergic diseases. A web-based questionnaire was posted to invite the participants who are members of the Japan Ophthalmologist Association and their family members. The answers from 3004 respondents were used to determine whether there were significant associations between the level of the pollutants and the prevalence of ocular allergic diseases. The study period was between March to May 2017. The data of the air pollutants during 2012 to 2016 were obtained from the National Institute for Environmental Studies. The prevalence of allergic diseases was calculated by post stratification and examined for significant associations with the level of pollutants using multiple logistic regression analyses. The prevalence of seasonal allergic conjunctivitis, perennial allergic conjunctivitis, atopic keratoconjunctivitis (AKC), and vernal keratoconjunctivitis (VKC) in Japan was 45.4%, 14.0%, 5.3%, and 1.2%, respectively. The high prevalence of the severe forms of allergic conjunctivitis, including AKC and VKC, were significantly associated with the levels of the air pollutants. The prevalence of AKC was significantly associated with the levels of NO 2 with an odds ratio (OR) of 1.23 (per quintile). The prevalence of VKC was significantly associated with the levels of NO x and PM 10 with ORs of 1.72 and 1.54 respectively. The significant associations between the prevalence of AKC and VKC and the levels of air pollutants indicate that clinicians need to be aware that air pollutants may pose serious risks of vision threatening severe ocular allergy.

Purpose: Local allergic rhinitis (LAR) has been reported in the field of otolaryngology; however, the concept of local allergic conjunctivitis (LAC) has not been widely studied in the ophthalmologic community. We routinely examined total IgE levels in tear fluids (t-tIgE) and antigen-specific IgE levels in serum (s-sIgE) in patients with suspected allergic conjunctivitis, on the basis of Japanese guidelines for allergic conjunctival diseases. There are several cases in which the results of t-tIgE and s-sIgE testing are divergent. We suggest that these divergent cases correspond to LAR in otolaryngology., Methods: The study included 148 patients (33 men and 115 women) with clinical symptoms and signs of allergic conjunctivitis. Allerwatch Tear IgE ® was used for measurement of t-tIgE levels. ImmunoCAP Rapid ® and View Allergy 39 ® were used for measurement of s-sIgE levels. Conjunctival cytology using spatula was used to identify eosinophils on the conjunctiva., Results: A total of 83 patients (56.1%) were positive and 65 patients were negative for t-tIgE in the AW. In the ICR, 97 patients (65.5%) were positive for at least one of the eight allergens, whereas 51 (34.5%) were negative for all allergens. Among 83 patients positive for t-tIgE, 14 (16.9%) had no detectable s-sIgE. Therefore, we considered the possibility of LAC in cases in which only local IgE could be detected. Among 28 cases (18.9%) who were negative for t-tIgE and s-sIgE, 21 underwent conjunctival scraping; eosinophils were found in four cases and eosinophilic granules in two. Accordingly, we considered the possibility of non-IgE-type AC in these six cases., Conclusions: These results suggest the existence of LAC that is a candidate of a phenotype of AC.

Aim: We investigated sublingual immunotherapy for mite-induced allergic rhinitis and its comorbid allergic conditions. Patients & methods: A prospective case-controlled study of 120 patients (case = 80, control = 40) over 12 months. Results: There was 53.6% reduction in total rhinitis symptom score (p < 0.0001), but not in controls (-7.3%, p = 0.99). The total symptom scores for concurrent asthma decreased from 17.79 to 8.8 (p < 0.0001); for allergic conjunctivitis from 20.89 to 10.0 (p = 0.0002); for atopic dermatitis from 46.40 to 29.38 (p = 0.0004) and 74.6% of patients weaned off nasal topical steroids. The treatment-related adverse reactions were mild and self-limiting. Conclusion: Though sublingual immunotherapy may be more expensive than conventional treatments, it was an adjunctive therapy that improved not only the outcomes for allergic rhinitis, but also its comorbid allergic conditions.