Background: The mannan-conjugated birch pollen polymerised allergoid EP-088_T502 has previously been shown to reduce allergic symptoms and anti-allergic medication use during the birch pollen season. This confirmatory phase III trial aimed to evaluate the efficacy, safety, tolerability, and immunologic effects of six pre-seasonal subcutaneous injections.Methods: In this DBPC trial, 278 participants with birch pollen–induced allergic rhinoconjunctivitis (ARC) received either placebo or a cumulative dose of 28,000 mTU EP-088_T502. The primary efficacy endpoint was the combined symptom and medication score (CSMS) during the peak birch pollen season. Safety, tolerability, health-related quality of life (QoL), and immunologic parameters were also assessed.Results: EP-088_T502 significantly reduced the CSMS during the peak birch pollen season compared with placebo (mean absolute difference [MAD] −0.31; p=0.016, FAS). In the PP and Complete Cases sets, MAD were -0.36 (p=0.012) and -0.51 (p=0.013), respectively. Health-related QoL improved by 20% in the EP-088_T502 group compared with placebo during the peak season (p<0.005). EP-088_T502 increased Bet v1-specific IgG4 levels after treatment compared with placebo (6.4-fold; p<0.0001). The Bet v1-specific IgE/IgG4 ratio was reduced by 73% from baseline and by 69% compared with placebo (both p<0.0001). Thirteen systemic allergic reactions occurred, including one grade III systemic reaction considered related to EP-088_T502.Conclusions: EP-088_T502 significantly improved symptom and medication scores in participants with birch pollen–induced ARC and induced a substantial Bet v1-specific IgG4 response. The higher cumulative dose was associated with enhanced immunologic effects and an acceptable safety and tolerability profile.

Systemic glucocorticosteroids (sGCS) are widely used in the treatment of chronic inflammatory airway diseases such as rhinitis, rhinosinusitis and asthma. It is well-known that systemic use is linked to multiple adverse effects (AEs) both in the short- and the long-term. However, less is known about the safety of multiple short courses of sGCS. Currently there is no established agreement on the acceptable cumulative exposure to sGCS, considering the potential for various AEs. This systematic review and meta-analysis evaluated sGCS-related AEs in both upper and lower inflammatory airway disease, with a particular focus on short- and long-term risks. We further evaluated whether a dose-response relationship existed between the daily and cumulative dosages of sGCS and the occurrence of those AEs. Our meta-analysis confirmed that cumulative dosages between 500 mg and 1 g prednisolone-equivalent significantly increase the risk of most AEs, with risks increasing with incremental dose. These findings underscore the importance of: (a) judicious sGCS prescription and need for steroid stewardship, due to their potential for short- and long-term complications, occurring even with repeated short courses, and (b) prioritization of steroid-sparing approaches (e.g., biologicals) to avoid reaching a cumulative dose of 500 mg.

Most Germans consider herbal medicinal products (HMPs) to be an important supplement to conventional medicine. Despite existing clinical evidence for safety and efficacy, they are still not sufficiently integrated into drug therapy of gynaecological complaints in everyday practice. By analysing patient-reported outcomes (PROs), this gap in medical care can be closed. Real-world data was extracted from the pharmaco-epidemiological database PhytoVIS. We analysed a sample (n = 1658) containing PROs from women who utilised HMPs to treat their gynaecological complaints applying descriptive and non-parametric bivariate statistical tests. Perceived effectiveness and tolerability of HMPs was rated as very good. For the treatment of menstrual complaints, Vitex agnus-castus L. was primarily used, and Actaea racemosa L. for menopausal complaints. Various herbal drugs were applied for uncomplicated urinary tract infections (uUTIs), but mainly Arctostaphylos uva-ursi (L.) Spreng. Regarding the pharmaceutical form, herbal teas were preferred for the treatment of uUTIs or by very young or elderly women. All other pharmaceutical forms were favoured for menstrual and menopausal complaints or middle-aged women. The pharmaceutical form did not impact the perceived therapeutic effectiveness. Our results provide valuable insights into patient preferences and show options for their integration into existing treatment strategies. By identifying the most popular and efficacious plants for certain gynaecological ailments, we support healthcare providers to better address the growing demand for complementary treatment options. This knowledge helps in tailoring healthcare to meet patient needs and to ensure the safety and efficacy of HMPs.

BACKGROUND:Mannan-conjugated allergoids represent an effective option for treating allergic diseases. This study evaluated the clinical impact of the mannan-conjugated, polymerised birch pollen allergoid EP-088_T502 in patients with birch pollen-induced allergic rhinoconjunctivitis over 3 years. METHODS:Following up to a double-blind, placebo-controlled dose-finding study, in this open, long-term extension study, 154 birch pollen-allergic patients were enrolled in Germany. Patients were treated with a cumulative dose of 48,000 mTU EP-088_T502 administered subcutaneously over five pre-seasonal visits in each of the two treatment years (2021, 2022) with a subsequent follow-up year in 2023. The primary efficacy endpoint was the combined symptom and medication score (CSMS) during the peak birch pollen season, which was compared with the CSMS of the placebo group during the peak pollen season of 2020. Safety, tolerability, and immunogenicity were also analysed. RESULTS:Compared to the placebo group of the preceding study, median CSMS during the peak birch pollen seasons showed reductions of 47.5% in 2021 (p < 0.001), 51.8% in 2022 (p < 0.001), and 36.5% in 2023 (p < 0.001). Median daily symptom scores were reduced by 40.7% in 2021 (p < 0.001), 40.7% in 2022 (p < 0.001), and 25.6% in 2023 (p < 0.010). Median daily medication scores reached 0.07 in 2021 and 0.04 in 2022 (p < 0.001) and were reduced by 65.9% in 2023 (p < 0.003). Immunological responses showed a 4.82-fold increase in Bet v1 sIgG4 (p = 0.001) and a marked decrease (-65.5%, p = 0.001) in the sIgE/sIgG4 ratio after the first treatment phase. EP-088_T502 demonstrated good safety and tolerability, with only six mild to moderate systemic allergic reactions (Grade I/II). No epinephrine was used. CONCLUSION:In this open-label study, two consecutive years of pre-seasonal short-course allergen immunotherapy (AIT) with EP-088_T502 markedly reduced symptoms and medication need in patients with birch pollen-induced rhinoconjunctivitis. Persistent therapeutic effects observed during the follow-up year, although limited by attrition of the study population, suggest sustained clinical improvement and indicate the potential disease-modifying impact of this treatment regimen.

ZUSAMMENFASSUNG Pflanzliche Arzneimittel (HMPs) werden häufig als Ergänzung zur konventionellen Medizin genutzt, jedoch noch unzureichend in die gynäkologische Standardtherapie integriert. Analyse von patientenberichteten Erfahrungen, um Anwendungsmuster, Wirksamkeit und Verträglichkeit von HMPs bei gynäkologischen Beschwerden besser zu verstehen. Auswertung realer Versorgungsdaten aus der pharmako-epidemiologischen Datenbank PhytoVIS (n=1658) mittels deskriptiver und bivariater nicht parametrischer Statistik. HMPs wurden insgesamt als sehr gut wirksam und verträglich bewertet. Bei Menstruationsbeschwerden wurde v. a. Vitex agnus-castus L., bei klimakterischen Beschwerden Actaea racemosa L. und bei unkomplizierten Harnwegsinfektionen v. a. Arctostaphylos uva-ursi (L.) Spreng. eingesetzt. Tees wurden bevorzugt bei Harnwegsinfekten sowie bei sehr jungen oder älteren Patientinnen, während andere Darreichungsformen eher bei Menstruations- und Wechseljahresbeschwerden genutzt wurden. Die Ergebnisse liefern Hinweise auf patientenrelevante Präferenzen und unterstützen die bessere Integration pflanzlicher Arzneimittel in gynäkologische Behandlungsstrategien zur bedarfsgerechten Versorgung.

BACKGROUND:Regulatory authorities recommend a combination of symptom and medication scores during the grass pollen season as a primary endpoint for Phase III allergen immunotherapy (AIT) trials targeting allergic rhinoconjunctivitis. However, many composite primary endpoint scales exist; none are validated, nor do they have a well-justified minimal clinically important difference (MCID). METHODS:Direct patient feedback from 1071 grass-allergic patients was obtained to determine the minimally relevant improvement in allergic symptoms and translated into an MCID for the EAACI recommended CSMS0-6. Additionally, a clinically relevant threshold for the validated Rhinitis Quality of Life Questionnaire (RQLQ(S)) was determined from studies of registered SLIT products and subsequently used as an anchor to derive the MCID for CSMS0-6 using the data of a Phase III clinical trial with PQ Grass 27,600 SU (RESONATE). RESULTS:69% of grass-allergic patients were satisfied with a 1-point-improvement (e.g., from "severe" to "moderate") in their most severe symptom. This translated into an MCID range for CSMS0-6 of -0.23 to -0.21 points or -17% to -16%. Furthermore, a -0.34 point difference in RQLQ(S) compared to placebo was justified as clinically meaningful based on Phase III data from 2 registered SLIT grass tablets. Using this RQLQ(S) threshold as an anchor, an MCID of CSMS0-6 of -0.21 points (-16%) was derived using RESONATE. CONCLUSIONS:Both patient feedback and RESONATE results support an average MCID of -0.22 points on the CSMS0-6 scale and -16% on a composite primary endpoint scale, providing minimal thresholds to be achieved after AIT compared to placebo to conclude a positive Phase III trial outcome.

Background: Allergen immunotherapy (IT) in Europe is generally administered as monoallergen IT. However, in some patients and in other parts of the world, multiallergen IT is common practice. A key question is whether allergens in a mixture retain their allergenicity over time. Objective: To demonstrate if allergenicity, as measured by skin-prick testing (SPT), is maintained after 6 months in a sublingual immunotherapy (SLIT) maintenance vial with three allergen extracts in a single individual vaccine, including two pollens and Dermatophagoides. Methods: We prepared two maintenance SLIT vials that contained mixed Dermatophagoides species (2000 AU/mL), ash tree and Bermuda grass pollens (1:50 w/v), one 6 months before SPT and the second 0-2 weeks before SPT, and three fresh vials (0-2 weeks before SPT) for each individual allergen. Duplicate SPTs were conducted with all five vials, diluent and positive (histamine 1 mg/mL) controls. Wheals were measured at 10 minutes (controls) and 20 minutes (allergen vaccines). The mean wheal diameter was calculated as the average of the longest and orthogonal diameters, i.e., (D1 + D₂)/2. For each allergen extract, two replicate wheals were obtained per participant; their mean diameters were averaged to yield a patient-level mean wheal diameter. These patient-level means were then averaged across all the participants. The paired t-test was used to calculate statistically significant differences between the mean wheal diameters of the extracts, with significance at p < 0.05. Results: The mean ± standard deviation wheal diameter produced by the 6-month-old and the fresh extracts were 8.7 ± 3.3 mm and 8.4 ± 2.87 mm, respectively. This difference was not significant. Moreover, the potency of both pollen extracts was conserved when mixed with house-dust mite extracts. Conclusion: In our pilot study, allergenicity of tree and grass pollen allergens in an allergen mix with Dermatophagoides in a SLIT maintenance vial was maintained over 6 months. Replication in a larger population would consolidate our findings.

Importance:Limited pharmaceutical options exist for preexposure prophylaxis of COVID-19 beyond vaccination. Azelastine, an antihistamine nasal spray used for decades to treat allergic rhinitis, has in vitro antiviral activity against respiratory viruses, including SARS-CoV-2. Objective:To determine the efficacy and safety of azelastine nasal spray for prevention of SARS-CoV-2 infections in healthy adults. Design, Setting, and Participants:A phase 2, double-blind, placebo-controlled, single-center trial was conducted from March 2023 to July 2024. Healthy adults from the general population were enrolled at the Saarland University Hospital in Germany. Interventions:Participants were randomly assigned 1:1 to receive azelastine, 0.1%, nasal spray or placebo 3 times daily for 56 days. SARS-CoV-2 rapid antigen testing (RAT) was conducted twice weekly, with positive results confirmed by polymerase chain reaction (PCR). Symptomatic participants with negative RAT results underwent multiplex PCR testing for respiratory viruses. Main Outcome:The primary end point was the number of PCR-confirmed SARS-CoV-2 infections during the study. Results:A total of 450 participants were randomized, with 227 assigned to azelastine and 223 to placebo; 299 (66.4%) were female, 151 (33.6%) male, with a mean (SD) age of 33.0 (13.3) years. Most were White (417 [92.7%]), with 4 (0.9%) African, 22 (4.9%) Asian, and 7 (1.6%) of other ethnicity. In the intention-to-treat (ITT) population, the incidence of PCR-confirmed SARS-CoV-2 infection was significantly lower in the azelastine group (n = 5 [2.2%]) compared with the placebo group (n = 15 [6.7%]) (OR, 0.31; 95% CI, 0.11-0.87). As secondary end points, azelastine demonstrated an increase in mean (SD) time to SARS-CoV-2 infection among infected participants (31.2 [9.3] vs 19.5 [14.8] days), a reduction of the overall number of PCR-confirmed symptomatic infections (21 of 227 participants vs 49 of 223 participants), and a lower incidence of PCR-confirmed rhinovirus infections (1.8% vs 6.3%). Adverse events were comparable between the groups. Conclusions and Relevance:In this single-center trial, azelastine nasal spray was associated with reduced risk of SARS-CoV-2 respiratory infections. These findings support the potential of azelastine as a safe prophylactic approach warranting confirmation in larger, multicentric trials. Trial registration:EudraCT number: 2022-003756-13.

Organ-specific allergen challenges are meant to reproduce the response of the airway mucosa to an allergen in a controlled manner [1]. Standardized protocols for nasal, conjunctival, and bronchial allergen challenges (NAC, CAC, and BAC, respectively) have been recently published by EAACI [2-4]. The NAC should be monitored by a combination of symptom score and objective measurement of nasal patency (through acoustic rhinometry, peak nasal inspiratory flow, etc.), and positivity is established by moderate changes in both parameters simultaneously or by clear changes in at least one parameter [2]. The cutoffs for moderate and clear changes rely on the method used to analyze the NAC [5, S1–S8] (Table 1). Conversely, CAC monitoring is based on the total ocular symptom score only, which evaluates redness, itching, tearing, and chemosis. Patients scoring ≥ 2 points in redness + itching or ≥ 5 points in the four symptoms after allergen instillation are considered positive [3]. Finally, BAC monitoring relies on lung function parameters only. A drop ≥ 20% in FEV1 respect to baseline identifies the early asthmatic response and is indicative of positivity [4]. For diagnostic purposes, one single allergen dose is administered during the NAC, whereas progressively increasing concentrations are given for BAC and CAC [1]. The administration of one allergen per session is generally recommended for allergen challenges, although a protocol with up to four allergens per session is also validated for NAC [S9]. Generally, a good asthma control (an asthma control test ≥ 20 points) is required for NAC and BAC, whereas more flexibility exists for CAC [1]. In any case, allergen challenges should be conducted by trained personnel and in a clinical setting equipped with resources to treat bronchoconstriction and perform resuscitation [1]. The diagnostic process for airway allergy should start with a thorough clinical history, interrogating the seasonality, persistence, and triggers of respiratory symptoms, besides the presence of allergic multimorbidity [2-4]. If the clinical history is suggestive or compatible with an allergic etiology, the patient should be subjected to atopy tests (skin prick test [SPT] and serum allergen-specific (s)IgE) [1]. In case of positive results to multiple allergenic sources, the quantification of serum sIgE against molecular allergens can help discriminate between genuine sensitization and cross-reactivity [S10]. Conversely, when atopy tests are negative, an allergen challenge can be conducted to identify local allergic phenotypes. Moreover, in some atopic individuals, the determination of sIgE against molecular allergens is not sufficient to clarify the discrepancies between the results of atopy tests and the pattern of respiratory symptoms. In this case, allergen challenges can help investigate the clinical relevance of sensitizations and/or identify concurrent allergies with negative atopy tests [2-4]. Of note, patients with chronic nasal symptoms can suffer from dual allergic rhinitis (combination of allergies with positive and negative atopy tests) or mixed rhinitis (combination of nonallergic mechanisms and allergies with positive atopy tests) [6], in addition to the allergic, local allergic, and nonallergic phenotypes (Figure 1). Because the NAC is safer and less time-consuming than the BAC [7], the former test can be considered to evaluate the impact of allergen exposure on the bronchial mucosa following a "united airway" approach (see Supporting Informaiton for further elaboration) [8, S11–S15]. The clinical implementation of allergen provocations faces several issues including the shortage of allergen-based reagents and the insufficient number of trained specialists, besides reimbursement policies and local regulations [1]. Interestingly, the concordance rate between the basophil activation test (BAT) and the NAC is very high for allergies with positive atopy tests (allergic rhinitis and systemic component of DAR) [9]. On the other hand, 25%–75% of allergies with negative atopy tests (local allergic rhinitis and local component of DAR) are associated with positive BAT results [6, 9, S16–S21]. Thus, the BAT can accurately replace the NAC for the confirmation of the clinical relevance of sensitizations, and it can save a significant amount of NAC for the identification of allergies with negative atopy tests. Nevertheless, a NAC will be still required in case of negative BAT results to rule in/out the allergic etiology in nonatopic individuals [9]. Of note, the BAT is a more patient-friendly technique than the NAC and does not require a wash-out period for anti-allergic medication. The identification of the allergic triggers of rhinitis, conjunctivitis, and asthma will facilitate the selection of candidates for allergen immunotherapy (AIT). Besides its long-term effect for allergies with positive atopy tests, AIT can also alleviate symptoms and improve the quality of life of patients with local respiratory allergy [10, S22–S28]. In this regard, serum sIgE against molecular allergens can aid the selection of AIT composition in atopic individuals [S10], whereas the BAT with molecular allergens has been proposed for the same purpose for allergies with negative atopy tests [S17, S21]. D.S.-T., A.T.-M., and G.B.-R. performed the literature review and extracted the main conclusions. M.J.T., R.M., and I.E.-G. drafted the manuscript and supervised the work of the other authors. The final version of this article was approved by all authors before submission. The authors declare no conflicts of interest. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Background Gynecological ailments have a negative impact on quality of life and productivity. Standard treatment is associated with poor tolerability and other issues related to public health and environment. Herbal Medicinal Products (HMPs) are used traditionally for the treatment of menstrual and menopausal ailments as well as uncomplicated urinary tract infections (uUTIs) for centuries and constitute a suitable addition to current treatment options. HMPs are well tolerated, non-polluting and therapeutically efficacious as evidenced by various clinical studies. Aim of this study was to expand the evidence regarding therapeutic effectiveness of HMPs for the treatment of gynecological complaints by complementing knowledge from clinical studies with real-world evidence from patient-reported outcomes. Methods A data set consisting of patient-reported outcomes regarding the treatment of gynecological ailments ( n = 1658) with HMPs was taken from the pharmaco-epidemiological database PhytoVIS. After data preparation excluding all cases of herbal supplements, homeopathic preparations, or non-herbal medicinal products the remaining data (n = 1363) was grouped into the three indications menstrual complaints ( n = 222), menopausal complaints ( n = 301), and uUTIs ( n = 840). We applied descriptive statistical methods (frequency and percentage) with regard to the variables “age”, “treatment duration”, “severity of symptoms”, “therapeutic benefits”, and “adverse drug reactions”. Thereafter we evaluated the therapeutic benefit of HMPs as well as adverse events. Results The majority of the patients (82.2%) in the sample assessed the overall therapeutic effect of HMPs for the treatment of gynecological complaints as beneficial and 90.8% of them perceived no or no significant adverse events. Treatment habits differed depending on the type of complaint. In this context the majority of women with menstrual or menopausal ailments preferred to treat for time period of 1 month or longer, while those affected by uUTIs reduced the application of HMPs to the length of their symptoms. Interestingly women with even strong symptoms relied on the therapeutic benefit of HMPs. Conclusion Real-world outcome data are an important supplement to clinical data. Our results reveal a favorable benefit-risk ratio of HMPs and help to implement them into novel therapeutic strategies to treat gynecological complaints.

Rationale: PQ Grass 27600 SU ist ein modifiziertes Breitspektrum-Grasallergen-SCIT-Produkt, das ein MCT-MPL-Adjuvans-System verwendet. Die optimale kumulative Dosis von PQ Grass 27600 SU wurde in der Phase-II-Dosisfindung auf der Grundlage einer statistisch hochsignifikanten Dosis-Wirkungs-Beziehung mit Plateaubildung ermittelt. Wir berichten hier über die Ergebnisse der pivotalen RESONATE-Studie, die zur Unterstützung des Zulassungsantrags durchgeführt wurde.