Quality of life in allergic rhinitis patients treated with intralymphatic immunotherapy (ILIT): A 19-year follow-up.

Background: In 2002-2005, we conducted a phase I/II clinical trial where a new allergy immunotherapy (AIT) route was introduced: intralymphatic immunotherapy (ILIT). Ultrasound guidance allowed injection of allergen directly into inguinal lymph nodes. Grass pollen-allergic patients received 3 injections with 1-month intervals. The short ILIT was more patient-friendly, required lower dosing, and was comparable with SCIT regarding short-term efficacy, which was used as a reference. Objective: Nineteen years after ILIT, the same patients were followed up to assess the long-term effect on quality of life and efficacy of the treatment. Methods: Patients who received ILIT and SCIT in 2002-2005 and an additional group of patients, who completed SCIT in 2015-2018, were recruited. All participants received a trial-specific in-house questionnaire and a standardized Rhinoconjunctivitis Quality of Life Questionnaire. Data were recorded off- (February 2021) and on- (May-June 2021) season. Descriptive statistics were applied. Results: Of 58 and 54 patients who originally received ILIT or SCIT, 25 (43%) and 29 (54%) patients, respectively, returned the questionnaires for analysis. Four (16%) and 3 (11%) of the ILIT and SCIT patients, respectively, developed complete protection against grass pollen-mediated rhinitis, whereas another 15 (60%) and 20 (69%) expressed satisfaction with the received AIT. In both groups, any persistent symptoms were reported as mild. Medication usage in the ILIT and SCIT groups was comparable. Nineteen (76%) and 23 (79%) patients, respectively, expressed satisfaction with their AIT. Conclusions: Grass pollen ILIT leads to long-term significant improvement in rhinitis-associated quality of life 19 years after treatment, and the ILIT quality-of-life effect was not inferior to that of SCIT.

Intralymphatic Immunotherapy (ILIT) With Bee Venom Allergens: A Clinical Proof-of-Concept Study and the Very First ILIT in Humans.

Background: Subcutaneous venom immunotherapy (VIT) represents an effective treatment against bee venom allergy. However, it involves long treatment times, high costs, and the risk of adverse events (AEs). Shorter, safer, and cheaper treatment options are therefore pursued. Objective: To determine the safety, immunogenicity, and efficacy of bee venom intralymphatic immunotherapy (ILIT). Methods: In an open pilot study, 12 patients received bee venom ILIT in three sessions with 14-day intervals: 0.1-5 µg/dose. Ultrasound imaging was applied to guide an injection and to document the lymph node structure. In a second study, 67 patients from 15 centers in Europe and Australia were randomized to receive four doses of either 10- or 20-µg bee venom ILIT with 28-day intervals. Clinical endpoints included specific IgE and IgG and protection after a bee sting challenge. These studies were performed in the years 2000-2003. Results: In a proof-of-concept study, no serious AEs were observed. An increase in allergen-specific IgG1 but no IgG4 and IgE was observed. ILIT induced the protection against a bee sting challenge in 7 out of 8 challenged patients. In a multicenter study, an increase in allergen-specific IgG and IgE was observed, with the highest increase in patients receiving a higher ILIT dose. The study was terminated due to several serious AEs upon the sting challenge provocation after the completion of treatment. However, out of 45 patients challenged, 15 (65%) and 18 (82%) patients in the 10- and 20-µg group, respectively, showed an improvement of two grades or more. No correlation was observed between antibody levels and sting protection. Conclusions: While a pilot study suggested the safety and efficacy of bee venom ILIT, a high number of AEs seen after the sting challenge following a randomized study indicate that the immunology protection offered by bee venom ILIT is insufficient. Of note, the bee venom allergen extract used in the two studies were from the two different providers. While the first study used a formulation approved for use in subcutaneous VIT, the second study used a nonapproved formulation never tested in humans. Further studies on approved formulations should be performed to generate conclusive results regarding the safety and efficacy of bee venom ILIT.

Immunization of Cats against Fel d 1 Results in Reduced Allergic Symptoms of Owners.

An innovative approach was tested to treat cat allergy in humans by vaccinating cats with Fel-CuMV (HypoCatTM), a vaccine against the major cat allergen Fel d 1 based on virus-like particles derived from cucumber mosaic virus (CuMV-VLPs). Upon vaccination, cats develop neutralizing antibodies against the allergen Fel d 1, which reduces the level of reactive allergen, thus lowering the symptoms or even preventing allergic reactions in humans. The combined methodological field study included ten cat-allergic participants who lived together with their cats (n = 13), that were immunized with Fel-CuMV. The aim was to determine methods for measuring a change in allergic symptoms. A home-based provocation test (petting time and organ specific symptom score (OSSS)) and a general weekly (or monthly) symptom score (G(W)SS) were used to assess changes in allergic symptoms. The petting time until a pre-defined level of allergic symptoms was reached increased already early after vaccination of the cats and was apparent over the course of the study. In addition, the OSSS after provocation and G(W)SS recorded a persistent reduction in symptoms over the study period and could serve for long-term assessment. Hence, the immunization of cats with HypoCatTM (Fel-CuMV) may have a positive impact on the cat allergy of the owner, and changes could be assessed by the provocation test as well as G(W)SS.

COVID-19 epidemic in Switzerland: on the importance of testing, contact tracing and isolation.

Switzerland is among the countries with the highest number of coronavirus disease-2019 (COVID-19) cases per capita in the world. There are likely many people with undetected SARS-CoV-2 infection because testing efforts are currently not detecting all infected people, including some with clinical disease compatible with COVID-19. Testing on its own will not stop the spread of SARS-CoV-2. Testing is part of a strategy. The World Health Organization recommends a combination of measures: rapid diagnosis and immediate isolation of cases, rigorous tracking and precautionary self-isolation of close contacts. In this article, we explain why the testing strategy in Switzerland should be strengthened urgently, as a core component of a combination approach to control COVID-19.

Legal and ethical framework for global health information and biospecimen exchange - an international perspective.

BACKGROUND: The progress of electronic health technologies and biobanks holds enormous promise for efficient research. Evidence shows that studies based on sharing and secondary use of data/samples have the potential to significantly advance medical knowledge. However, sharing of such resources for international collaboration is hampered by the lack of clarity about ethical and legal requirements for transfer of data and samples across international borders. MAIN TEXT: Here, the International Clinical Trial Center Network (ICN) reports the legal and ethical requirements governing data and sample exchange (DSE) across four continents. The most recurring requirement is ethical approval, whereas only in specific conditions approval of national health authorities is required. Informed consent is not required in all sharing situations. However, waiver of informed consent is only allowed in certain countries/regions and under certain circumstances. The current legal and ethical landscape appears to be very complex and under constant evolution. Regulations differ between countries/regions and are often incomplete, leading to uncertainty. CONCLUSION: With this work, ICN illuminates the unmet need for a single international collaborative framework to facilitate DSE. Harmonising requirements for global DSE will reduce inefficiency and waste in research. There are many challenges to realising this ambitious vision, including inconsistent terminology and definitions, and heterogeneous and dynamic legal constraints. Here, we identify areas of agreement and significant difference as a necessary first step towards facilitating international collaboration. We propose the establishment of a working group to continue the comparison across jurisdictions, create a standardised glossary and define a set of basic principles and fundamental requirements for DSE.

Immunization of cats to induce neutralizing antibodies against Fel d 1, the major feline allergen in human subjects.

BACKGROUND: Cat allergy in human subjects is usually caused by the major cat allergen Fel d 1 and is found in approximately 10% of the Western population. Currently, there is no efficient and safe therapy for cat allergy available. Allergic patients usually try to avoid cats or treat their allergy symptoms. OBJECTIVE: We developed a new strategy to treat Fel d 1-induced allergy in human subjects by immunizing cats against their own major allergen, Fel d 1. METHODS: A conjugate vaccine consisting of recombinant Fel d 1 and a virus-like particle derived from the cucumber mosaic virus containing the tetanus toxin-derived universal T-cell epitope tt830-843 (CuMVTT) was used to immunize cats. A first tolerability and immunogenicity study, including a boost injection, was conducted by using the Fel-CuMVTT vaccine alone or in combination with an adjuvant. RESULTS: The vaccine was well tolerated and had no overt toxic effect. All cats induced a strong and sustained specific IgG antibody response. The induced anti-Fel d 1 antibodies were of high affinity and exhibited a strong neutralization ability tested both in vitro and in vivo. A reduction in the endogenous allergen level and a reduced allergenicity of tear samples, were observed. CONCLUSION: Vaccination of cats with Fel-CuMVTT induces neutralizing antibodies and might result in reduced symptoms of allergic cat owners. Both human subjects and animals could profit from this treatment because allergic cat owners would reduce their risk of developing chronic diseases, such as asthma, and become more tolerant of their cats, which therefore could stay in the households and not need to be relinquished to animal shelters.

Intralymphatic Immunotherapy: Update and Unmet Needs.

Allergen-specific immunotherapy (AIT) is the only allergy treatment that confers long-term symptom amelioration for patients suffering from allergy. The most frequently used allergen application route is subcutaneous injection (SCIT), commonly taken as the gold standard, followed by sublingual (SLIT) or oral (OIT) application of allergen preparations. This is an up-to-date review of the clinical evidence for a novel route of allergen application, i.e., directly into lymph nodes - intralymphatic immunotherapy (ILIT). The major advantages of ILIT over the current AIT approaches are its short duration and the low allergen doses administered. The whole treatment consists of merely 3 ultrasound-guided injections into inguinal lymph nodes 1 month apart. While the number of patients included in randomised controlled trials is still limited, the clinical results for ILIT are encouraging, but more clinical trials are needed, as well as more preclinical work for optimising formulations.

Allergen immunotherapy in allergic rhinitis: current use and future trends.

INTRODUCTION: Type-1 allergies are among the most chronic common diseases of humans. Allergen immunotherapy (AIT) is the only causative and disease-modifying treatment option besides allergen avoidance. Severe systemic adverse allergic reactions may be induced by every AIT treatment. Different approaches have been used to provide safer AIT preparations to lower or even totally overcome this risk. Areas covered: A structured literature recherche in Medline and Pubmed under inclusion of national and international guidelines and Cochrane meta-analyses has been performed aiming at reviewing clinical use of such approaches in AIT. New allergen preparations may include allergoids, recombinant allergens (recA) and modified recombinant allergens (recA) in subcutaneous as well as in mucosal immunotherapies (application e.g. using bronchial, nasal, oral and sublingual application) with sublingual being the established mucosal application route and new ways of application like intralymphatic and epicutaneous immunotherapy. Expert commentary: Immune-modifying agents like Virus-like particles and CpG-motifs, adjuvants like MPL and aluminum hydroxide are evaluated and found to increase and direct the immunological response toward immunological tolerance. New forms of allergen extracts can improve safety and efficacy of AIT and may change our way of performing allergen immunotherapy in the future.

Novel Delivery Routes for Allergy Immunotherapy: Intralymphatic, Epicutaneous, and Intradermal.

Current allergy immunotherapy protocols suffer from two main problems: long treatment duration and systemic allergic side effects of the allergen administrations. The immunologic effects of allergen administration could be enhanced and the number of allergen administrations and treatment duration reduced by choosing a tissue for administration that contains a high density of antigen-presenting cells. Local side effects could be reduced by choosing a route characterized by a low density of mast cells, and systemic side effects could be reduced by administration to nonvascularized tissues, so that inadvertent systemic distribution of the allergen and consequent systemic allergic side effects are minimized.

Comparison of microneedles and adhesive-tape stripping in skin preparation for epicutaneous allergen delivery.

BACKGROUND: Epicutaneous immunotherapy targets the network of dendritic cells in the epidermis. Allergen exposure of the dermal layers should be limited as these contain mast cells and blood vessels, which increases the risk for local and systemic allergic reactions. METHODS: This intraindividually controlled trial included 20 subjects with birch pollen allergy. Three areas of the volar forearms were treated by repeated adhesive-tape stripping, single-prick lancet piercing and microneedle array application. Four 10-fold dilutions of allergen extract were applied to each area and the IgE-mediated immediate-phase reactions and cell-mediated eczema were assessed. RESULTS: Allergen application after tape stripping led to an immediate-phase reaction in 2 subjects (10%) at the highest allergen concentration of 10 HEP/ml. Both prick needle and microneedle pretreatment resulted in immediate-phase reactions in all subjects (100%). The reactivity pattern, however, differed significantly: 95% of the reactions after pricking occurred at concentrations of ≤0.1 HEP/ml, whereas 50% of the reactions after microneedle preparation were noted at ≥1 HEP/ml. In 3 subjects (15%), eczema was observed on the microneedle-treated skin area. No serious adverse events occurred. CONCLUSIONS: Microneedles enhance stratum corneum penetration when compared to tape stripping. However, they do not resolve the problem of mast cell-mediated local reactions, possibly due to diffusion into the dermis. The occurrence of eczema after the microneedle treatment suggests induction of dendritic cell-mediated T cell responses. Therefore, skin preparation with microneedles may be a promising method for epicutaneous allergen immunotherapy.

Intralymphatic immunotherapy.

Gold Standard allergen-specific immunotherapy is associated with low efficacy because it requires either many subcutaneous injections of allergen or even more numerous sublingual allergen administrations to achieve amelioration of symptoms. Intralymphatic vaccination can maximize immunogenicity and hence efficacy. We and others have demonstrated that as few as three low dose intralymphatic allergen administrations are sufficient to effectively alleviate symptoms. Results of recent prospective and controlled trials suggest that this strategy may be an effective form of allergen immunotherapy.

Is The Allergen Really Needed in Allergy Immunotherapy?

Immunotherapy for type I allergies is well established and is regarded to be the most efficient treatment option besides allergen avoidance. As of today, different forms of allergen preparations are used in this regard, as well as different routes of application. Virus-like particles (VLPs) represent a potent vaccine platform with proven immunogenicity and clinical efficacy. The addition of toll-like receptor ligands and/or depot-forming adjuvants further enhances activation of innate as well as adaptive immune responses. CpG motifs represent intensively investigated and potent direct stimulators of plasmacytoid dendritic cells and B cells, while T cell responses are enhanced indirectly through increased antigen presentation and cytokine release. This article will focus on the function of VLPs loaded with DNA rich in nonmethylated CG motifs (CpGs) and the clinical experience gained in the treatment of allergic rhinitis, demonstrating clinical efficacy also if administered without allergens. Several published studies have demonstrated a beneficial impact on allergic symptoms by treatment with CpG-loaded VLPs. Subcutaneous injection of VLPs loaded with CpGs was tested with or without the adjuvant alum in the presence or absence of an allergen. The results encourage further investigation of VLPs and CpG motifs in immunotherapy, either as a stand-alone product or as adjuvants for allergen-specific immunotherapy.

Epicutaneous Immunotherapy for Aeroallergen and Food Allergy.

IgE-mediated allergies today affect up to 30 % of the population in industrialized countries. Allergen immunotherapy is the only disease-modifying treatment option with a long-term effect. However, very few patients (<5 %) choose immunotherapy, due to the long treatment duration (between 3-5 years) and possible local and systemic allergic side effects of the allergen administrations. The latter occur when an allergen accidentally reaches the blood circulation. Therefore, the ideal application route for allergen immunotherapy should be characterized by two hallmarks: firstly, by a high number of potent antigen-presenting cells, which enhance efficacy and thus shorten treatment duration. Secondly, the allergen administration site is ideally non-vascularized, so that inadvertent systemic distribution of the allergen and consequent systemic allergic side effects are minimized. The epidermis contains high numbers of potent antigen-presenting Langerhans cells and, as an epithelium, is non-vascularized. Therefore, the epidermis represents an interesting administration route. Historical evidence for the clinical efficacy of epicutaneous allergy immunotherapy (EPIT) has now been strengthened by a number of recent double-blinded placebo-controlled clinical trials performed by independent groups. We review the immunological rationale, history and clinical experience with epicutaneous allergy immunotherapy.

Influence of phytase, EDTA, and polyphenols on zinc absorption in adults from porridges fortified with zinc sulfate or zinc oxide.

Fortification of cereal staples with zinc is recommended to combat zinc deficiency. To optimize zinc absorption, strategies are needed to overcome the inhibitory effect of phytic acid (PA) and perhaps polyphenols. Five zinc absorption studies were conducted in young adults consuming maize or sorghum porridges fortified with 2 mg zinc as zinc sulfate (ZnSO4) or zinc oxide (ZnO) and containing combinations of PA or polyphenols as potential inhibitors and EDTA and phytase as potential enhancers. Fractional absorption of zinc (FAZ) was measured by using the double isotopic tracer ratio method. Adding phytase to the maize porridge immediately before consumption or using phytase for dephytinization during meal preparation both increased FAZ by >80% (both P < 0.001). Adding Na2EDTA at an EDTA:zinc molar ratio of 1:1 increased FAZ from maize porridge fortified with ZnSO4 by 30% (P = 0.01) but had no influence at higher EDTA ratios or on absorption from ZnO. FAZ was slightly higher from ZnSO4 than from ZnO (P = 0.02). Sorghum polyphenols had no effect on FAZ from dephytinized sorghum porridges but decreased FAZ by 20% from PA-rich sorghum porridges (P < 0.02). The combined inhibitory effect of polyphenols and PA was overcome by EDTA. In conclusion, ZnSO4 was better absorbed than ZnO, phytase used to degrade PA during digestion or during food preparation substantially increased zinc absorption from zinc-fortified cereals, EDTA at a 1:1 molar ratio modestly enhanced zinc absorption from ZnSO4-fortified cereals but not ZnO-fortified cereals, and sorghum polyphenols inhibited zinc absorption in the presence, but not absence, of PA. This trial was registered at clinicaltrials.gov as NCT01210794.

Immunotherapy of type-1 allergies with virus-like particles and CpG-motifs.

Immunotherapy of type-I-allergies is regarded as the most efficient treatment option besides allergen avoidance. Different forms of allergen preparations are used as well as different routes of application. Virus-like particles represent a potent vaccine platform with proven immunogenicity and clinical efficacy. The addition of toll-like receptor ligands and/or depot-forming adjuvants further enhances immune cell activation. This article will focus on the function of virus-like particles loaded with DNA rich in CpG-motifs and discuss clinical experience in treatment of allergic rhinitis. Evidence will be presented that clinically effective treatment can be obtained even in the absence of allergens. Results encourage further investigation of virus-like particles and CpG-motifs in immunotherapy, either as a stand alone product, or as adjuvants for allergen-specific immunotherapy.

A randomized, double-blind, placebo-controlled study to test the efficacy of topical 2-hydroxypropyl-Beta-cyclodextrin in the prophylaxis of recurrent herpes labialis.

Herpes labialis affects one third of the population. We evaluated the topical application of an antiviral compound, hydroxypropyl-ß-cyclodextrin (2-HPßCD), in reducing herpes labialis relapses. In this double-blind, randomized, placebo-controlled trial, 40 patients were randomized to a polyethylene glycol (PEG) formulation containing 20% 2-HPßCD or to a vehicle control arm. The gel was applied to the lips twice daily for 6 months. The primary objective was reducing herpes relapses. Surprisingly, the drug group had significantly more relapses than the vehicle group (p = 0.003). While the median numbers of relapses in the preceding year were 12 in the vehicle group and 10 in the drug group, both groups experienced very few relapses during the 6-month treatment period, with a median of 0 in the vehicle group and a median of 2 in the drug group. The impressive reduction of relapses in both groups may be due to a placebo effect or due to the topical treatment with PEG.

Risk assessment of Hymenoptera re-sting frequency: implications for decision-making in venom immunotherapy.

BACKGROUND: Venom immunotherapy is highly efficacious in preventing anaphylactic sting reactions. However, there is an ongoing discussion regarding patient selection and whether and how to apply a cost-benefit analysis of venom immunotherapy. In order to help decision-making, we investigated the re-sting frequency of hymenoptera-venom-allergic patients to single out those at high risk. METHODS: In this retrospective study, re-sting data of 96 bee-venom-allergic patients and 95 vespid-venom-allergic patients living mainly in a rural area of Switzerland were analyzed. Hymenoptera venom allergy status was rated according to the classification system of H.L. Mueller [J Asthma Res 1966;3:331-333]. Different risk-groups were defined according to sting exposure and their median sting-free interval was calculated. RESULTS: The risk factors for a wasp or bee re-sting were outdoor occupation, beekeeping and habitation close to a bee-house. Half of all vespid-venom-allergic outdoor workers were re-stung within 3.75 years compared to 7.5 years for indoor workers. Similarly, 50% of the bee-venom-allergic beekeepers or subjects with a bee-house in the vicinity suffered a bee re-sting within 5.25 years compared to 10.75 years for individuals who were not beekeepers. CONCLUSIONS: The high degree of exposure of vespid-venom-allergic outdoor workers and bee-venom-allergic beekeepers and subjects living close to bee-houses underlines the high benefit of venom immunotherapy for these patients even if they suffered a non-life-threatening grade II reaction. Yet, bee-venom-allergic individuals with no proximity to bee-houses and with an indoor occupation face a very low exposure risk, which justifies epinephrine rescue treatment for these patients especially if they have suffered from grade II sting reactions.

EAACI: A European Declaration on Immunotherapy. Designing the future of allergen specific immunotherapy.

Allergy today is a public health concern of pandemic proportions, affecting more than 150 million people in Europe alone. In view of epidemiological trends, the European Academy of Allergy and Clinical Immunology (EAACI) predicts that within the next few decades, more than half of the European population may at some point in their lives experience some type of allergy.Not only do allergic patients suffer from a debilitating disease, with the potential for major impact on their quality of life, career progression, personal development and lifestyle choices, but they also constitute a significant burden on health economics and macroeconomics due to the days of lost productivity and underperformance. Given that allergy triggers, including urbanization, industrialization, pollution and climate change, are not expected to change in the foreseeable future, it is imperative that steps are taken to develop, strengthen and optimize preventive and treatment strategies.Allergen specific immunotherapy is the only currently available medical intervention that has the potential to affect the natural course of the disease. Years of basic science research, clinical trials, and systematic reviews and meta-analyses have convincingly shown that allergen specific immunotherapy can achieve substantial results for patients, improving the allergic individuals' quality of life, reducing the long-term costs and burden of allergies, and changing the course of the disease. Allergen specific immunotherapy not only effectively alleviates allergy symptoms, but it has a long-term effect after conclusion of the treatment and can prevent the progression of allergic diseases.Unfortunately, allergen specific immunotherapy has not yet received adequate attention from European institutions, including research funding bodies, even though this could be a most rewarding field in terms of return on investments, translational value and European integration and, a field in which Europe is recognized as a worldwide leader. Evaluation and surveillance of the full cost of allergic diseases is still lacking and further progress is being stifled by the variety of health systems across Europe. This means that the general population remains unaware of the potential use of allergen specific immunotherapy and its potential benefits.We call upon Europe's policy-makers to coordinate actions and improve individual and public health in allergy by:Promoting awareness of the effectiveness of allergen specific immunotherapyUpdating national healthcare policies to support allergen specific immunotherapyPrioritising funding for allergen specific immunotherapy researchMonitoring the macroeconomic and health economic parameters of allergyReinforcing allergy teaching in medical disciplines and specialtiesThe effective implementation of the above policies has the potential for a major positive impact on European health and well-being in the next decade.