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Introduction: Eosinophil‐derived neurotoxin (EDN) is a biomarker for eosinophilic activation. Urinary (u) EDN may allow non‐invasive monitoring of asthma, but clinical recommendations are lacking. We assessed the potential of uEDN as a marker of disease activity in pediatric asthma. Method s : We assessed urine samples of 371 children from the German ALLIANCE study cohort, from which we had: 169 preschool wheezers (<6 years), 80 asthmatics (≥6 years), and 122 healthy controls using the ImmunoCAP™ EDN Assay. Creatinine (Cr)‐adjusted uEDN values were analyzed using correlations, association tests, (non) parametric statistics, multiple linear, and multivariable regression. Results: uEDN/uCr values were higher in atopic versus non‐atopic preschool‐aged subjects (p =.035) and associated with the sum of allergen‐specific IgE in younger (r = 0.24, p =.003), and older subjects (r = 0.23, p =.043). uEDN/uCr was marginally a good determinant for atopy (p =.078, for subjects aged <6 years, and p =.058 for subjects ≥6 years). Children with the T2‐high phenotype had higher uEDN/uCr (p <.001) versus T2‐low—irrespective of using uEDN/uCr or blood eosinophils in combination to allergen sIgE for disease phenotyping. uEDN/uCr significantly correlated with reduced lung function among asthmatics (FEV1 z‐scores: r = −0.30, p =.007, and FEV1/FVC z‐scores: r = −0.24, p =.038). Using multivariable modeling, uEDN/uCr was an independent determinant of FEV1 (p =.038), and to a lesser extent, FEV1/FVC (p =.080). Conclusions: uEDN/uCr may serve as a non‐invasive biomarker for clinical features such as lung function in pediatric asthma. We highlight the utility of uEDN/uCr as a biomarker that can be easily assessed using widely available robust diagnostic immunoassays. [ABSTRACT FROM AUTHOR]

Background: Current in vitro allergen‐specific IgE (sIgE) detection assays measure IgE against allergen extracts or molecules in a single‐ or multiplex approach. Direct comparisons of the performance of such assays among young children with common presentations of allergic diseases regardless of sensitization status are largely missing. Objectives: The aim of this study was a comparison of the analytical and diagnostic performance for common clinical questions of three commonly used technologies which rely upon different laboratory methodologies among children of the All Age Asthma (ALLIANCE) cohort (clinicaltrials.gov: NCT02496468). Methods: Sera from 106 paediatric study participants (mean age 4 years) were assessed for the presence of sIgE by means of the ImmunoCAP™ sx1 and fx5 mixes, the ImmunoCAP ISAC™ 112 microarray and a Euroline™ panel. Results: Total and negative concordance was high (>82%–>89%), while positive concordance varied considerably (0%–100%) but was also >50% for the most common sensitizations analysed (house dust mite and birch). All three test systems showed good sensitivity and specificity (AUC consistently > 0.7). However, no significant differences with regard to identifying sIgE sensitizations associated with symptoms in children with suspected pollen‐ or dust‐triggered wheeze or presenting with symptoms of allergic rhinoconjunctivitis or food allergy were detected. Extending the number of allergens did not change the similar performance of the three assay systems. Conclusion and Clinical Relevance: Among young children, the three sIgE assays showed good analytical and diagnostic concordance. Our results caution that the identification of larger numbers of sensitizations by more comprehensive multiplex approaches may not improve the clinical utility of sIgE testing in this age group. [ABSTRACT FROM AUTHOR]

Almost half of all preterm births are caused or triggered by an inflammatory process at the feto-maternal interface resulting in preterm labor or rupture of membranes with or without chorioamnionitis ("first inflammatory hit"). Preterm babies have highly vulnerable body surfaces and immature organ systems. They are postnatally confronted with a drastically altered antigen exposure including hospital-specific microbes, artificial devices, drugs, nutritional antigens, and hypoxia or hyperoxia ("second inflammatory hit"). This is of particular importance to extremely preterm infants born before 28 weeks, as they have not experienced important "third-trimester" adaptation processes to tolerate maternal and self-antigens. Instead of a balanced adaptation to extrauterine life, the delicate co-regulation between immune defense mechanisms and immunosuppression (tolerance) to allow microbiome establishment is therefore often disturbed. Hence, preterm infants are predisposed to sepsis but also to several injurious conditions that can contribute to the onset or perpetuation of sustained inflammation (SI). This is a continuing challenge to clinicians involved in the care of preterm infants, as SI is regarded as a crucial mediator for mortality and the development of morbidities in preterm infants. This review will outline the (i) role of inflammation for short-term consequences of preterm birth and (ii) the effect of SI on organ development and long-term outcome. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Numerous products are available for subcutaneous (SCIT) and sublingual allergen-specific immunotherapy, but there are no information about the direct comparability regarding efficacy, safety, and tolerability of the different extracts. Aims: The aim of this open-labelled, prospective, controlled observational trial was to test the feasibility of a comparison of different products for SCIT in children. Methods: Pediatrician practices recruited patients with a confirmed diagnosis of a seasonal allergic rhinoconjunctivitis (AR) with or without asthma and an allergic sensitization against grass pollen allergen. Every patient was offered SCIT with one out of six allergen extracts: ALK SQ Depot, ALK Avanz, Allergovit, Depigoid, Purethal, Pollinex Quattro. Scores for symptoms and medications were calculated and the difference between treatment years and baseline were recorded. Results: In total, 284 were recruited and 255 children (89.8%; mean age 10.4, SD 3.54 years; 65% males) participated in this trial. Overall, 49,649 patient days were recorded in the electronic database (mean 183.2 days/patient). There was no significant difference in the AR and asthma symptom score or the medication score between the six different SCIT preparations. Similarly, no differences were observed in terms of safety and tolerability. Conclusion: The comparison of different SCIT products using an online tool is feasible. Based on our preliminary data, all extracts indicated efficacy; however, larger groups would be necessary to demonstrate superiority or non-inferiority of one specific SCIT product. [ABSTRACT FROM AUTHOR]

Kopp MV, Mayatepek E, Engels E, Brauburger J, Riedinger F, Ihorst G, Wahn U, Kuehr J. Urinary leukotriene E4 levels in children with allergic rhinitis treated with specific immunotherapy and Anti-IgE (Omalizumab). Pediatr Allergy Immunol 2003: 14: 401–404. © 2003 Blackwell Munksgaard Recently, we were able to demonstrate that Omalizumab, a humanized monoclonal anti-IgE antibody, reduces in vitro leukotriene (LT) release of peripheral leukocytes stimulated with allergen in children with allergic rhinitis undergoing allergen immunotherapy. The aim of this study was to investigate the effect of anti-IgE in combination with specific immunotherapy (SIT) on urinary leukotriene E4 (LTE4) levels. Children and adolescents with sensitization to birch and grass pollens and suffering from seasonal allergic rhinitis were included in a phase III, placebo-controlled, multicenter clinical study. Within the four-arm study, patients were randomized to receive SIT for either birch or grass pollen and to receive either subcutaneous anti-IgE or placebo for 24 weeks during the pollen season. From a total population of 225 children, we collected three urine samples in a subgroup of 19 children [n = 12 boys (63%); mean age 11.8 years; range 7.2–17.5 years; Group A (n = 10): SIT (grass or birch) + anti-IgE; Group B (n = 9): SIT (grass or birch) + placebo]. Urine samples were collected before, during and at the end of treatment. Endogenous urinary LTE4 was separated by high-performance liquid chromatography (HPLC) and determined by enzyme immunoassay with a specific antibody. No differences in urinary LTE4 concentrations were observed between the anti-IgE and the placebo groups before (A: 35.2; B: 36.5 nmol/mol creatinine), during (A: 27.0; B: 29.3) and after treatment (A: 28.9; B: 26.5 nmol/mol creatinine). We conclude that urinary LTE4 levels are not helpful in monitoring patients treated with anti-IgE and SIT. [ABSTRACT FROM AUTHOR]

Background: Pediatric community acquired pneumonia (pedCAP) is one of the leading causes for childhood morbidity accounting for up to 20% of pediatric hospital admissions in high income countries. In spite of its high morbidity, updated epidemiological and pathogen data after introduction of preventive vaccination and novel pathogen screening strategies are limited. Moreover, there is a need for validated recommendations on diagnostic and treatment regimens in pedCAP. Through collection of patient data and analysis of pathogen and host factors in a large sample of unselected pedCAP patients in Germany, we aim to address and substantially improve this situation.Methods: pedCAPNETZ is an observational, multi-center study on pedCAP. Thus far, nine study centers in hospitals, outpatient clinics and practices have been initiated and more than 400 patients with radiologically confirmed pneumonia have been enrolled, aiming at a total of 1000 study participants. Employing an online data base, information on disease course, treatment as well as demographical and socioeconomical data is recorded. Patients are followed up until day 90 after enrollment; Comprehensive biosample collection and a central pedCAPNETZ biobank allow for in-depth analyses of pathogen and host factors. Standardized workflows to assure sample logistics and data management in more than fifteen future study centers have been established.Discussion: Through comprehensive epidemiological, clinical and biological analyses, pedCAPNETZ fills an important gap in pediatric and infection research. To secure dissemination of the registry, we will raise clinical and scientific awareness at all levels. We aim at participating in decision making processes for guidelines and prevention strategies. Ultimately, we hope the results of the pedCAPNETZ registry will help to improve care and quality of life in pedCAP patients in the future. [ABSTRACT FROM AUTHOR]

Rationale: The strongest genetic risk factor for childhood-onset asthma, the 17q21 locus, is associated with increased viral susceptibility and disease-promoting processes. Objectives: To identify biological targets underlying the escalated viral susceptibility associated with the clinical phenotype mediated by the 17q21 locus. Methods: Genome-wide transcriptome analysis of nasal brush samples from 261 children (78 healthy, 79 with wheezing at preschool age, 104 asthmatic) within the ALLIANCE (All-Age-Asthma) cohort, with a median age of 10.0 (range, 1.0-20.0) years, was conducted to explore the impact of their 17q21 genotype (SNP rs72163891 ). Concurrently, nasal secretions from the same patients and visits were collected, and high-sensitivity mesoscale technology was employed to measure IFN protein levels. Measurements and Main Results: This study revealed that the 17q21 risk allele induces a genotype- and asthma/wheeze phenotype-dependent enhancement of mucosal GSDMB expression as the only relevant 17q21-encoded gene in children with preschool wheeze. Increased GSDMB expression correlated with the activation of a type-1 proinflammatory, cell-lytic immune, and natural killer signature, encompassing key genes linked to an IFN type-2-signature ( IFNG , CXCL9 , CXCL10 , KLRC1 , CD8A , GZMA ). Conversely, there was a reduction in IFN type 1 and type 3 expression signatures at the mRNA and protein levels. Conclusions: This study demonstrates a novel disease-driving mechanism induced by the 17q21 risk allele. Increased mucosal GSDMB expression is associated with a cell-lytic immune response coupled with compromised airway immunocompetence. These findings suggest that GSDMB -related airway cell death and perturbations in the mucosal IFN signature account for the increased vulnerability of 17q21 risk allele carriers to respiratory viral infections during early life, opening new options for future biological interventions.The All-Age-Asthma (ALLIANCE) cohort is registered at www.clinicaltrials.gov (pediatric arm, NCT02496468).

Background: Paediatric community-acquired pneumonia (CAP) is a leading cause of paediatric morbidity. However, particularly for outpatients with paediatric CAP, data on aetiology and management are scarce., Methods: The prospective pedCAPNETZ study multicentrically enrols children and adolescents with outpatient-treated or hospitalised paediatric CAP in Germany. Blood and respiratory specimens were collected systematically, and comprehensive analyses of pathogen spectra were conducted. Follow-up evaluations were performed until day 90 after enrolment., Results: Between December 2014 and August 2020, we enrolled 486 children with paediatric CAP at eight study sites, 437 (89.9%) of whom had radiographic evidence of paediatric CAP. Median (interquartile range) age was 4.5 (1.6-6.6) years, and 345 (78.9%) children were hospitalised. The most prevalent symptoms at enrolment were cough (91.8%), fever (89.2%) and tachypnoea (62.0%). Outpatients were significantly older, displayed significantly lower C-reactive protein levels and were significantly more likely to be symptom-free at follow-up days 14 and 90. Pathogens were detected in 90.3% of all patients (one or more viral pathogens in 68.1%; one or more bacterial strains in 18.7%; combined bacterial/viral pathogens in 4.1%). Parainfluenza virus and Mycoplasma pneumoniae were significantly more frequent in outpatients. The proportion of patients with antibiotic therapy was comparably high in both groups (92.4% of outpatients versus 86.2% of hospitalised patients)., Conclusion: We present first data on paediatric CAP with comprehensive analyses in outpatients and hospitalised cases and demonstrate high detection rates of viral pathogens in both groups. Particularly in young paediatric CAP patients with outpatient care, antibiotic therapy needs to be critically debated., Competing Interests: Conflict of interest: M. Wetzke received funding from the Young Academy Clinician/Scientist foundation Hannover Medical School, Germany and the Clinical Leave Clinician/Scientist program of the German Center for Infection Research (DZIF). K. Schütz and G. Hansen received funding from the Deutsche Forschungsgemeinschaft for the Cluster of Excellence EXC2155 “RESIST” project (ID 39087428). C. Happle received funding from the Young Academy Clinician/Scientist foundation and HiLF funding of Hannover Medical School, Germany, and the Excellence Cluster RESIST in infection research. M.V. Kopp, G. Hansen and T. Welte received funding from the German Center for Lung Research (DZL). The other authors received no additional funding. The authors have no conflicts of interests for this article to disclose., (Copyright ©The authors 2023.)

Background: Comprehensive studies investigated the role of T-cells in asthma which led to personalised treatment options targeting severe eosinophilic asthma. However, little is known about the contribution of B-cells to this chronic inflammatory disease. In this study we investigated the contribution of various B-cell populations to specific clinical features in asthma., Methods: In the All Age Asthma Cohort (ALLIANCE), a subgroup of 154 adult asthma patients and 28 healthy controls were included for B-cell characterisation by flow cytometry. Questionnaires, lung function measurements, blood differential counts and allergy testing of participants were analysed together with comprehensive data on B-cells using association studies and multivariate linear models., Results: Patients with severe asthma showed decreased immature B-cell populations while memory B-cells were significantly increased compared with both mild-moderate asthma patients and healthy controls. Furthermore, increased frequencies of IgA + memory B-cells were associated with impaired lung function and specifically with parameters indicative for augmented resistance in the peripheral airways. Accordingly, asthma patients with small airway dysfunction (SAD) defined by impulse oscillometry showed increased frequencies of IgA + memory B-cells, particularly in patients with mild-moderate asthma. Additionally, IgA + memory B-cells significantly correlated with clinical features of SAD such as exacerbations., Conclusions: With this study we demonstrate for the first time a significant association of increased IgA + memory B-cells with asthma and SAD, pointing towards future options for B-cell-directed strategies in preventing and treating asthma., Competing Interests: Conflict of interest: C. Happle reports grants from Novartis and Pari, outside the submitted work. M.V. Kopp reports grants from Allergopharma GmbH and Vertex GmbH; honoraria for lectures from Allergopharma GmbH, Sanofi GmbH, Infectopharm GmbH, Vertex GmbH and Leti GmbH; advisory board membership at Allergopharma GmbH and Sanofi GmbH; outside the submitted work. E. von Mutius reports royalties from Elsevier GmbH, Georg Thieme Verlag, Springer-Verlag GmbH and Elsevier Ltd; consulting fees from the Chinese University of Hong Kong, European Commission, HiPP GmbH & Co KG and AstraZeneca; lecture honoraria from Massachusetts Medical Society, Springer-Verlag GmbH, Elsevier Ltd, Boehringer Ingelheim International GmbH, European Respiratory Society, Universiteit Utrecht – Faculteit Diergeneeskunde, Universität Salzburg, Springer Medizin Verlag GmbH, Japanese Society of Pediatric Allergy and Clinical Immunology (JSPACI), Klinikum Rechts der Isar, University of Colorado, Paul-Martini-Stiftung and Imperial College London; travel support from Verein zur Förderung der Pneumologie am Krankenhaus Großhansdorf eV, Pneumologie Développement, Mondial Congress & Events GmbH & Co. KG, American Academy of Allergy, Asthma & Immunology, Imperial College London, Margaux Orange, Volkswagen Stiftung, Boehringer Ingelheim International GmbH, European Respiratory Society, Universiteit Utrecht – Faculteit Diergeneeskunde, Österreichische Gesellschaft für Allergologie und Immunologie, Massachusetts Medical Society, OM Pharma SA, Hanson Wade Ltd, iKOMM GmbH, DSI Dansk Borneastma Center, American Thoracic Society, HiPP GmbH & Co. KG and Universiteit Utrecht – Faculteit Bètawetenschappen; outside the submitted work. In addition, E. von Mutius has patent LU101064 (Barn dust extract for the prevention and treatment of diseases) pending, royalties paid to ProtectImmun for patent EP2361632 (Specific environmental bacteria for the protection from and/or the treatment of allergic, chronic inflammatory and/or autoimmune disorders, granted on 19 March 2014), and patents EP1411977 (Composition containing bacterial antigens used for the prophylaxis and the treatment of allergic diseases, granted on 18 April 2007), EP1637147 (Stable dust extract for allergy protection, granted on 10 December 2008) and EP1964570 (Pharmaceutical compound to protect against allergies and inflammatory diseases, granted on 21 November 2012) licensed to ProtectImmun. In addition, E. von Mutius is a member of the EXPANSE (funded by European Commission) Scientific Advisory Board, member of the BEAMS External Scientific Advisory Board (ESAB), member of the Editorial Board of the Journal of Allergy and Clinical Immunology: In Practice, member of the Scientific Advisory Board of the Children's Respiratory and Environmental Workgroup (CREW), member of the International Scientific and Societal Advisory Board (ISSAB) of Utrecht Life Sciences (ULS), University of Utrecht, member of the External Review Panel of the Faculty of Veterinary Science, University of Utrecht, member of the Selection Committee for the Gottfried Wilhelm Leibniz Programme (DFG), member of the International Advisory Board of the Asthma UK Centre for Applied Research (AUKCAR), member of the International Advisory Board of The Lancet Respiratory Medicine, and member of the Scientific Advisory Board of the CHILD (Canadian Healthy Infant Longitudinal Development) study, McMaster University, Hamilton, Canada. T. Bahmer reports grants from Network University Medicine (NUM): National Pandemic Cohort Network (NAPKON); consulting fees and lecture honoraria from AstraZeneca, Novartis, GlaxoSmithKline, Roche and Chiesi; travel support from Chiesi and AstraZeneca; outside the submitted work. K.F. Rabe reports lecture honoraria from AstraZeneca, Boehringer Ingelheim, Chiesi Pharmaceuticals, Novartis, Sanofi Regeneron, GlaxoSmithKline, Berlin-Chemie and Roche; advisory board membership at AstraZeneca and Sanofi Regeneron; leadership roles with the German Center for Lung Research (DZL), German Chest Society (DGP) and American Thoracic Society; outside the submitted work. A. Meyer-Bahlburg reports lecture honoraria from Pfizer; travel support from CSL Behring; advisory board membership with Pfizer; outside the submitted work. G. Hansen reports consulting fees from Sanofi GmbH; lecture honoraria from MedUpdate and AbbVie; outside the submitted work. All other authors have nothing to disclose., (Copyright ©The authors 2022.)

Not available., (© Dustri-Verlag Dr. K. Feistle.)

Background: Asthma is a heterogeneous syndrome substantiating the urgent requirement for endotype-specific biomarkers. Dysbalance of fibrosis and fibrolysis in asthmatic lung tissue leads to reduced levels of the inflammation-protective collagen 4 (COL4A3)., Objective: To delineate the degradation of COL4A3 in allergic airway inflammation and evaluate the resultant product as a biomarker for anti-IgE therapy response., Methods: The serological COL4A3 degradation marker C4Ma3 (Nordic Bioscience, Denmark) and serum cytokines were measured in the ALLIANCE cohort (paediatric cases/controls: n=134/n=35; adult cases/controls: n=149/n=31). Exacerbation of allergic airway disease in mice was induced by sensitising to ovalbumin (OVA), challenge with OVA aerosol and instillation of poly(cytidylic-inosinic). Fulacimstat (chymase inhibitor; Bayer) was used to determine the role of mast cell chymase in COL4A3 degradation. Patients with cystic fibrosis (n=14) and cystic fibrosis with allergic bronchopulmonary aspergillosis (ABPA; n=9) as well as patients with severe allergic uncontrolled asthma (n=19) were tested for COL4A3 degradation. Omalizumab (anti-IgE) treatment was assessed using the Asthma Control Test., Results: Serum levels of C4Ma3 were increased in asthma in adults and children alike and linked to a more severe, exacerbating allergic asthma phenotype. In an experimental asthma mouse model, C4Ma3 was dependent on mast cell chymase. Serum C4Ma3 was significantly elevated in cystic fibrosis plus ABPA and at baseline predicted the success of the anti-IgE therapy in allergic, uncontrolled asthmatics (diagnostic OR 31.5)., Conclusion: C4Ma3 levels depend on lung mast cell chymase and are increased in a severe, exacerbating allergic asthma phenotype. C4Ma3 may serve as a novel biomarker to predict anti-IgE therapy response., Competing Interests: Conflict of interest: M. Weckmann reports grants from Federal Ministry for Education and Research (BMBF), University of Lübeck (E42-2012 and JC01-2016) and German Academic Exchange Service (56266000), during the conduct of the study. Conflict of interest: T. Bahmer has nothing to disclose. Conflict of interest: J.M. Sand is a full-time employee of Nordic Bioscience. Conflict of interest: S. Rank Rønnow is employed by Nordic Bioscience, and has received grants from Innovation Foundation, during the conduct of the study. Conflict of interest: M. Pech has nothing to disclose. Conflict of interest: C. Vermeulen has nothing to disclose. Conflict of interest: A. Faiz has nothing to disclose. Conflict of interest: D.J. Leeming is a stockholder and full-time employee of Nordic Bioscience A/S. Conflict of interest: M.A. Karsdal is a stockholder and full-time employee of Nordic Bioscience. Conflict of interest: L. Lunding has nothing to disclose. Conflict of interest: B.G.G. Oliver has nothing to disclose. Conflict of interest: M. Wegmann has nothing to disclose. Conflict of interest: G. Ulrich-Merzenich reports grants for research and meeting attendance from Novartis AG, during the conduct of the study; and has a patent EPC 18185472.0-1118 pending. Conflict of interest: U.R. Juergens has nothing to disclose. Conflict of interest: J. Duhn has nothing to disclose. Conflict of interest: Y. Laumonnier has nothing to disclose. Conflict of interest: O. Danov has nothing to disclose. Conflict of interest: K. Sewald has nothing to disclose. Conflict of interest: U. Zissler reports grants and personal fees from Federal Ministry for Education and Research of Germany, during the conduct of the study. Conflict of interest: M. Jonker has nothing to disclose. Conflict of interest: I. König has nothing to disclose. Conflict of interest: G. Hansen is a consultant for Novartis and Sanofi. Conflict of interest: E. von Mutius received consultancy fees from European Commission, Tampereen Yliopisto, University of Edinburgh, Nestec S.A., University of Veterinary Medicine, Vienna, Chinese University of Hongkong, Research Center Borstel – Leibniz Lung Center, OM Pharma S.A., Pharmaventures Ltd, Peptinnovate Ltd, Turun Yliopisto, Helsingin Yliopisto, Chinese University of Hongkong, Imperial College London, Universiteit Utrecht, Universität Salzburg, Österreichische Gesellschaft f. Allergologie u. Immunologie, HiPP GmbH & Co KG; received fees for speaking from Japanese Society of Pediatric Allergy and Clinical Immunology (JSPACI), The American Academy of Allergy Asthma and Immunology, British Society for Immunology, Medical University of Vienna, Schweizerisches Institiut für Allergie- und Asthmaforschung, Howard Hughes Medical Institute, University Hospital Erlangen, Margaux Orange, Deutsche Akademie der Naturforscher Leopoldina e.V., Hannover Medical School, American Thoracic Society, Inc., European Academy of Allergy and Clinical Immunology, Mundipharma Deutschland GmbH & Co. KG, DOC Congress SRL, ITÄ-Suomen Yliopisto, Interplan – Congress, Meeting & Event Management AG, INC, Ökosoziales Forum Oberösterreich, Imperial College London, WMA Kongress GmbH, University Hospital rechts der Isar, European Respiratory Society, HAL Allergie GmbH, PersonalGenomes.org, Nestlé Deutschland AG, Universitätsklinikum Aachen, SIAF – Swiss Institute of Allergy and Asthma Research, Deutsche Pharmazeutische Gesellschaft e.V., Verein zur Förderung der Pneumologie am Krankenhaus Großhansdorf e.V., Pneumologie Developpement, Mondial Congress & Events GmbH & Co. KG, Volkswagen Stiftung, Boehringer Ingelheim International GmbH, Hanson Wade Ltd, DSI Dansk Borneastma Center; received author honoraria from Elsevier Ltd, Springer-Verlag GmbH, Schattauer GmbH, Georg Thieme Verlag, Springer Medizin Verlag GmbH; is on the editorial board of the New England Journal of Medicine; and has a patent Application number LU101064, Barn dust extract for the prevention and treatment of diseases pending; a patent Publication number EP2361632: Specific environmental bacteria for the protection from and/or the treatment of allergic, chronic inflammatory and/or autoimmune disorders with royalties paid to Protectimmun GmbH; a patent Publication number EP 1411977: Composition containing bacterial antigens used for the prophylaxis and the treatment of allergic diseases licensed to Protectimmun GmbH; a patent Publication number EP1637147: Stable dust extract for allergy protection licensed to Protectimmun GmbH; and a patent Publication number EP 1964570: Pharmaceutical compound to protect against allergies and inflammatory diseases licensed to Protectimmun GmbH. Conflict of interest: O. Fuchs is a consultant for Menarini and Vifor; has received speaker's fees from Vertex, aha! Allergy Centre Switzerland, Menarini, Novartis, Medical Tribune Switzerland, German Society of Paediatric Allergology and ALK; and has received travel support from Milupa/Nutricia, Stallergenes Greer and Bencard. Conflict of interest: A-M. Dittrich has nothing to disclose. Conflict of interest: B. Schaub reports grants from DFG, BMBF and EU, outside the submitted work. Conflict of interest: C. Happle has nothing to disclose. Conflict of interest: K.F. Rabe received grants from Boehringer Ingelheim and personal fees from AstraZeneca, Novartis, Sanofi, Regeneron, Roche and Chiesi Pharmaceuticals. Conflict of interest: M. van de Berge reports grants paid to university from GlaxoSmithKline, AstraZeneca and Genentech, outside the submitted work. Conflict of interest: J.K. Burgess reports grants from National Health and Medical Research Council, Australia, University of Groningen and European Union, during the conduct of the study. Conflict of interest: M.V. Kopp reports grants from Federal Ministry of Research and Education (BMBF), during the conduct of the study; personal fees from ALK-Abello, Allergopharma, Boehringer Ingelheim, Chiesi, Glaxo, Infectopharm, Meda, Sanofi-Aventis, Leti Pharma, Novartis and Vertex, outside the submitted work., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: It is estimated that up to 24% of the population in Germany suffers from allergic rhinoconjunctivitis and 5% from allergic asthma. Allergic rhinoconjunctivitis is closely related to other atopic diseases., Methods: This review is based on pertinent publications retrieved by a selective search of the Medline database, guidelines from Germany and abroad, and Cochrane meta-analyses., Results: Specific immunotherapy (SIT) is the only diseases-modifying treatment option for allergies. Meta-analysis reveals standardized mean differences in allergic rhinitis symptom scores of -0.73 for subcutaneous immunotherapy (SCIT) and -0.49 for sublingual immunotherapy (SLIT); the corresponding mean differences in medication scores are -0.57 and -0.32, respectively. The treatment should be carried out for at least three years. It is indicated when the symptoms are severe and allergen avoidance is not a realistic option. The efficacy of treatment depends on the allergen dose; thus, every allergen preparation should be evaluated individually, independent of route of administration. SCIT can cause systemic adverse effects, including anaphylaxis. SLIT is safer but often causes allergic symptoms of the oral mucosa at the beginning of treatment., Conclusion: Even though the efficacy of SIT is well documented, it is still underused. SIT should be offered as standard treatment to patients suffering from allergic rhinitis.

Novel therapies that interfere specifically with immunological mechanisms underlying allergen-induced pathology are currently in clinical evaluation. Among these is anti-IgE, which directly targets IgE serum antibodies, thus inhibiting the central mechanism of immediate type hypersensitivity reactions. Application of anti-IgE antibodies effectively reduces IgE serum levels regardless of allergen specificity. It has been successfully tested in patients with allergic rhinitis, asthma and food allergy, showing significant efficacy in reducing symptom scores and use of rescue medications. Anti-IgE therapy is limited by high costs and the requirements for permanent or every-season treatment. The advantage of specific immune therapy (SIT) is the potential to alter the course of the disease, which has been demonstrated in patients with allergic rhinitis, insect venom allergy and, to a lesser degree, with asthma. The broader application of SIT is restricted by sometimes life-threatening side-effects. Here, we summarize the results of clinical trials investigating the effects of combination therapy with anti-IgE and SIT in patients with rhinitis and asthma. These studies show that combination of anti-IgE plus SIT may be beneficial for the treatment of allergic diseases by improving efficacy and limiting side effects.