This systematic review evaluates the efficacy and safety of biologicals for chronic rhinosinusitis with nasal polyps (CRSwNP) compared to the standard of care. Pubmed, EMBASE and Cochrane Library were searched for RCTs. Critical and important CRSwNP-related outcomes were considered. The risk of bias and the certainty of the evidence were assessed using GRADE. RCTs evaluated (dupilumab-2, omalizumab-4, mepolizumab-2, reslizumab-1) included 1236 adults, with follow-up 20-64 weeks. Dupilumab reduces the need for surgery (NFS) and oral corticosteroid (OCS) use (RR 0.28; 95%CI 0.20-0.39, moderate certainty) and improves with high certainty smell (mean difference (MD) +10.54; 95%CI +9.24 to +11.84) and quality of life (QoL) (MD -19.14; 95%CI 95%CI -22.80 to -15.47), with fewer treatment-related adverse events (TAEs) (RR 0.95; 95%CI 0.89-1.02, moderate certainty). Omalizumab reduces NFS (RR 0.85; 95%CI 0.78 to 0.92, high certainty), decreases OCS use (RR 0.38; 95%CI 0.10-1.38, moderate certainty), improves with high certainty smell (MD +3.84; 95%CI +3.64 to +4.04) and QoL (MD -15.65; 95%CI -16.16 to -15.13), with increased TAE (RR 1.73; 95%CI 0.60-5.03, moderate certainty). There is low certainty for mepolizumab reducing NFS (RR 0.78; 95%CI 0.64 to 0.94) and improving QoL (MD -13.3; 95% CI -23.93 to -2.67) and smell (MD +0.7; 95%CI -0.48 to +1.88), with increased TAEs (RR 1.64; 95%CI 0.41-6.50). The evidence for reslizumab is very uncertain.
Background. First vaccines for prevention of Coronavirus disease 2019 (COVID-19) are becoming available but there is a huge and unmet need for specific forms of treatment. In this study we aimed to evaluate the potent anti-SARS-CoV-2 effect of siRNA both in vitro and in vivo. Methods. To identify most effective molecule out of a panel of 15 in silico designed siRNAs, an in vitro screening system based on vectors expressing SARS-CoV-2 genes fused with the firefly luciferase reporter gene and SARS-CoV-2-infected cells was used. The most potent siRNA, siR-7, was modified by Locked nucleic acids (LNAs) to obtain siR-7-EM with increased stability and was formulated with the peptide dendrimer KK-46 for enhancing cellular uptake to allow topical application by inhalation of the final formulation - siR-7-EM/KK-46. Using the Syrian Hamster model for SARS-CoV-2 infection the antiviral capacity of siR-7-EM/KK-46 complex was evaluated. Results. We identified the siRNA, siR-7, targeting SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) as the most efficient siRNA inhibiting viral replication in vitro. Moreover, we have shown that LNA-modification and complexation with the designed peptide dendrimer enhanced the antiviral capacity of siR-7 in vitro. We demonstrated significant reduction of virus titer and total lung inflammation in the animals exposed by inhalation of siR-7-EM/KK-46 in vivo. Conclusions. Thus, we developed a therapeutic strategy for COVID-19 based on inhalation of a modified siRNA-peptide dendrimer formulation.
Higher risk of allergies at 4-6 years of age after systemic antibiotics in the first week of life To the editor,In humans, the first 100 days appear to be a ”critical window” of colonization during which microbial communities shape immune maturation.1,2. The use of antibiotics early in life may disrupt the normal maturation process leading to adverse health outcomes such as atopic disorders 1,3-5. The effects of antibiotic exposure immediately in the first week of life have rarely been investigated, nor the differences between treatment of 2-3 days and a prolonged treatment of 5-7 days. In the INCA study, a prospective birth cohort study of 151 infants receiving broad-spectrum antibiotics in their first week of life (AB+), and 285 healthy controls (AB-), we previously showed that antibiotic treatment in the first week of life was associated with an increased risk of wheezing, infantile colic and a trend towards more allergic sensitization in the first year of life6. The aim of this follow-up study in 418 eligible children was to determine if antibiotic treatment in the first week of life in term-born children was associated with an increase in atopic disorders at 4-6 years of age, using ISAAC questionnaires filled out by parents, ICPC codes derived from general physicians, and pharmaceutical records from local pharmacies. Detailed information regarding the subjects and methods is described in the online Appendix.In total, 341 of 418 (82%) questionnaires were filled out (114 AB+ and 227 AB-), Parental reported allergy was significantly higher in AB+ vs AB- children (23% vs 11% respectively, p=0.003) as was doctor-diagnosed allergy (12% vs 4% respectively, p=0.008). Confirmed food allergies were more common in AB+ children compared with AB- children (10 vs. 4% respectively, p=0.03). After correcting for sex, age, daycare attendance, family atopy, and parental level of education, parental-reported allergy was clearly associated with antibiotics use in the first week of life (aOR 2.40 [95%CI 1.22-4.72, p=0.01]). Additional adjustment for treatment duration showed that only 5-7 and not 2-3 days AB treatment was associated with a higher risk of parental reported allergy (aOR 2.85 [95%CI 1.37-5.91, p=0.005]). More importantly, this effect was independent of exposure to acid-suppressive drugs or additional antibiotics in the first two years of life (36% and 35% in AB- and AB+ group, respectively). The prevalence of eczema, wheezing/asthma, or allergic rhinitis was not different between AB+ and AB- children (Table 2).These results suggest that very early exposure to AB in the first week of life has a higher impact on microbiota and immune development than when administered later in childhood. It also emphasizes the need for judicious use of AB in neonates, especially prolonged treatment of 5-7 days. Moreover, our findings accentuate the need for finding strategies to modify microbiome development after AB exposure to minimize aberrant immune development.Strengths of this study are the prospective design, the high response rate (82%), and the combined information collected from doctors and pharmacists, contributing to the reliability of the reported results, which allowed us to distinguish between the effect of antibiotics within and after the first week of life. A limitation of the study is the 4-6-year follow-up, which may have been too short for diagnosing asthma and allergic rhinitis.In conclusion, the risk of having an allergy at 4-6 years of age increased nearly 3-fold in children after antibiotic treatment for 5-7 days in their first week of life, independent of later AB treatment. These long-term adverse health effects of neonatal antibiotic use emphasize the need to implement AB stewardship programs to avoid AB overuse and reduce the duration of AB treatment where possible in the first week of life.
Vaccines are essential public health tools with a favorable safety profile and prophylactic effectiveness that have historically played significant roles in reducing infectious disease burden in populations, when the majority of individuals are vaccinated. The COVID-19 vaccines are expected to have similar positive impacts on health across the globe. While serious allergic reactions to vaccines are rare, their underlying mechanisms and implications for clinical management should be considered to provide individuals with the safest care possible. In this review, we provide an overview of different types of allergic adverse reactions that can potentially occur after vaccination and individual vaccine components capable of causing the allergic adverse reactions. We present the incidence of allergic adverse reactions during clinical studies and through post-authorization and post-marketing surveillance and provide plausible causes of these reactions based on potential allergenic components present in several common vaccines. Additionally, we review implications for individual diagnosis and management and vaccine manufacturing overall. Finally, we suggest areas for future research.
Background: The success of subcutaneous immunotherapy (SCIT) mostly depends on regular injections. Our aim was to investigate adherence to SCIT with aeroallergens during the COVID-19 pandemic and demonstrate clinical consequences of treatment disruptions in real-life. Methods: Visual analogue scale for quality of life (VAS-QoL), VAS for symptom scores (VAS-symptom), medication scores (MSs) and total symptom scores (TSS-6) were recorded during the pandemic in 327 adult allergic rhinitis and/or asthmatic patients receiving maintenance SCIT and these scores were compared with the pre-pandemic data. Patients were grouped according to SCIT administration intervals; no delay (Group 1), <2 months (Group 2), and ≥2 month intervals (Group 3). Results: 104 (31.8%) patients (Group 3) were considered as non-adherent which was mostly related to receiving SCIT with HDMs and using public transportation for reaching the hospital. Median MS, VAS-symptom and TSS-6 scores of Group 3 patients during the pandemic were higher than the pre-pandemic scores (p=0.005, p<0.001, p<0.001, respectively) whereas median VAS-QoL scores of Group 3 during the pandemic were lower than the pre-pandemic scores (p<0.001). Median TSS-6 and VAS-symptom scores were the highest in Group 3 compared to other groups (p<0.001 for each comparison). Median VAS-QoL scores were the lowest in Group 3 compared to Group 1 and Group 2 (p<0.001, p=0.043, respectively). Conclusion: When precautions in allergy clinics are carefully applied, adherence to SCIT can be high during a pandemic. Patients must be warned about adhering to SCIT injections since delays in SCIT administration can deteriorate clinical symptoms.
Medical Algorithm: Diagnosis and Managemen of Humoral ImmunodeficienciesAnna Šedivá1, Tomáš Milota1, Jiří Litzman2, Isabella Quinti3, ESID Clinical Working Party, EAACI Primary Immunodeficiency Working Group, Stephen Jolles4Department of Immunology, 2nd Faculty of Medicine Charles University, V Uvalu, University Hospital in Motol, Prague, Czech RepublicFaculty of Medicine, Masaryk University Brno, Czech Republic; Department of Clinical Immunology and Allergology, St Anne´s University Hospital, Brno, Czech RepublicDepartment of Molecular Medicine, Sapienza University of Rome, Rome, ItalyImmunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, UKFor ESID Clinical Working Party:Isabelle Meyts, Department of Pediatrics, Leuven University Hospitals, Leuven, BelgiumSiobhan Burns, Institute of Immunity and Transplantation, University College London, London, United Kingdom; Department of Immunology, Royal Free London NHS Foundation Trust, London, United KingdomAuthor´s contributions:AS prepared the concept and wrote the manuscript, TM edited Figures and wrote the manuscript, JL designed Figures and revised manuscript, IQ designed Figures and revised the manuscript, IM revised manuscript, SB revised manuscript, ST edited Figures and wrote the manuscript.
Article type: News and Views: Groundbreaking Discoveries in ImmunologyTitle: Uncovering the influence of diet and gut microbiota in human serum metabolomeAuthors: David Obeso1,2‡, Elisa Zubeldia-Varela1,2‡ and Alma Villaseñor11Instituto de Medicina Molecular Aplicada (IMMA), Departamento de Ciencias Médicas Básicas. Facultad de Medicina. Universidad San Pablo-CEU, CEU Universities, Madrid, España.2Centro de Metabolómica y Bioanálisis (CEMBIO), Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Madrid, España.‡: These Authors have equally contributedCorrespondence: Alma Villaseñor, Centro de Metabolómica y Bioanálisis (CEMBIO), Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Madrid, EspañaEmail address:[email protected]: Metabolomics, Diet, Microbiota, Allergy, Serum, MetabolomeAbbreviations: MS, mass spectrometry; LC, liquid chromatography; short chain fatty acids (SCFA)Acknowledgement: We would like to thank Anna Głobińska for her assistance in generating the graphical figure. AV Gratefully acknowledges the Martín-Carbajo family for supporting her scientific development through the X Mario Martín Velamazán award.Author contributions: D.O., E.Z-V. and A.V contributed to the writing of the manuscript and have given approval to the manuscript. A.V. supervised the final version.
Although there is a considerable body of knowledge about allergen immunotherapy (AIT), there is a lack of data on the reliability of real-world evidence (RWE) in AIT and consequently, a lack of information on how AIT effectively works in real life. To address the current unmet need for an appraisal of the quality of RWE in AIT, the European Academy of Allergy and Clinical Immunology Methodology Committee recently initiated a systematic review of observational studies of AIT, which will use the RELEVANT tool and the Grading of Recommendations Assessment, Development and Evaluation approach (GRADE) to rate the quality of the evidence base as a whole. The next step will be to develop a broadly applicable, pragmatic “real-world” database using systematic data collection. Based on the current RWE base, and perspectives and recommendations of authorities and scientific societies, a hierarchy of RWE in AIT is proposed, which places pragmatic trials and registry data at the positions of highest level of evidence. There is a need to establish more AIT registries that collect data in a cohesive way, using standardised protocols. This will provide an essential source of real-world data that can be easily shared, promoting evidence-based research and quality improvement in study design and clinical decision-making.
Letter to EditorTo the EditorEgg-allergic children have higher ovomucoid (OVM)-specific IgD (sIgD) levels compared to the atopic controls.1 Within the egg-allergic group, children with higher levels of OVM-sIgD have a decreased risk of anaphylactic reactions. Ovalbumin (OVA)-sIgD increases in egg-allergic children desensitized by oral immunotherapy (OIT) but not in children unresponsive to OIT or with sustained unresponsiveness to OVA challenge.2 The natural development of tolerance and the acquisition of sustained unresponsiveness by OIT in egg-allergic children are associated with an increase in OVM-specific IgG4 (sIgG4) levels and a decrease in OVM-specific IgE (sIgE) levels.3 To elucidate the potential role of IgD in the outgrowing of egg allergy, we analyzed levels of egg white (EW)-, OVM-, and OVA-sIgD and sIgG4 in sera from 57 egg-allergic children (28 avoided all forms of egg in the diet (complete avoidance of egg: CAE), 18 were able to ingest at least 1/32 cooked whole egg but not one cooked whole egg (partial avoidance of egg: PAE), and 11 outgrew egg allergy (OGE)) and 23 healthy non-egg allergic children (non-egg allergy: NEA) (Table S1). The study was approved by The Research Ethics Committee of University of Fukui (#20110052), and written informed consent was obtained from the parent or guardians.EW-, and OVM-sIgE levels measured using ImmunoCAP (Thermo-Fisher Inc., MA) were higher in the CAE group, followed by the PAE, OGE, and NEA groups (Fig 1, Fig S1). The CAE group exhibited lower serum levels of EW- and OVA-sIgD compared to the NEA group and the PAE group, respectively, and had the lowest OVM-sIgD serum levels among all groups, suggesting that OVM-sIgD levels are associated with outgrowing egg allergy. We observed the lowest serum levels of EW-, OVA-, and OVM-sIgG4 in the CAE group, followed by the PAE and OGE groups. The ratio of OVM-sIgD to OVA-sIgD increased as children outgrew egg allergy, whereas the ratio of OVM-sIgG4 to OVA-sIgG4 did not change. Thus, the production of OVM-sIgD differs from OVM-sIgG4 as children naturally outgrow egg allergy.High-affinity, but not low-affinity, IgE is known to cause anaphylaxis.4 High-affinity IgE is derived from memory IgG1+ B cells, whereas low-affinity IgE is derived from naïve IgM+IgD+ B cells. Considering class switching pathways, switching direction from IgM to IgD, and from IgG1 to IgE or IgG4, elevated OVM-sIgD levels might be associated with low-affinity OVM-sIgE levels as children outgrow egg allergy, resulting in hypo-responsiveness to OVM.A recent study found that OVM-sIgE avidity was more effective at differentiating clinically reactive egg-allergic patients from those tolerant of heated egg compared to EW-sIgE.5 The ratio of OVM-sIgE to OVM-sIgD or sIgG4 in the CAE group was significantly higher compared to the PAE, OGE, and NEA groups (Fig 2). Receiver operating analysis revealed that the ratio of OVM-sIgE to OVM-sIgD discriminated non-tolerant from partially-tolerant egg-allergic patients with the largest area under the curve (AUC = 0.965) compared with levels of OVM-sIgE or the ratio of OVM-sIgE to OVM-sIgG4. The optimal cutoff for the ratio of OVM-sIgE to OVM-sIgD had 86.5% sensitivity and 96.4% specificity to identify high-risk subjects (Table S2).There are several limitations to this study. First, there was a small number of patients. Second, all children were only challenged with heated egg and were instructed to avoid egg of any form if they tested positive with less than 1/32 cooked whole egg. Finally, there was a lack of trajectory of sIgD levels during natural tolerance development.In conclusion, the ratio of OVM-sIgE to OVM-sIgD is a useful marker to identify high-risk egg-allergic patients capable of ingesting a low-dose of cooked whole egg who might be a good candidate for low-dose OIT.
Additional Features of Food Induced Immediate Reaction in the Esophagus (FIRE) in a Series of Adult Patients with Eosinophilic EsophagitisTo the EditorEosinophilic esophagitis (EoE) is a chronic disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil predominant inflammation. The predominant symptom in adults with active EoE is solid food dysphagia due to the high incidence of esophageal stricture formation. A quantitative tool has been developed to characterize the nature of these symptoms (1). Most typically patients complain of food going down slowly, food getting stuck and pain. These symptoms are most likely to occur during the passage of dense solid foods such as meats, bread and rice.Recently a phenomenon with a different symptom referred to as FIRE (food induced immediate reaction in the esophagus) has been described in adults with EoE. (2). Patients with eosinophilic esophagitis describe these esophageal symptoms as distinct from dysphagia. The symptoms typically occur after the food has been swallowed with rapid onset esophageal discomfort often described as tightening or pressure but without the sense of dysphagia. A large series of Swiss patients with eosinophilic esophagitis were queried via a form mailed to their homes or in clinics concerning symptoms related an immediate reaction in the esophagus distinct from dysphagia (2). A significant portion (49%) reported some form of esophageal discomfort related to eating. Although certain subject characteristics in this study such as younger age of onset of EoE and higher prevalence of allergies was noted, detailed clinical information on each subject was not available for review. Here in we described a series of patients with biopsy proven eosinophilic esophagitis who describe characteristic symptoms of FIRE following a specific food ingestion. For each selected FIRE patient a detailed chart review was conducted characterizing their demographics and EoE history (Table 1) as well as characteristics of their FIRE profile (Table 2). A number of features were noted in this group of 8 EoE patients as a previously unrecognized symptom complex. The onset of symptoms most often occurred within 1-60 minutes (median 3.5 minutes) after ingestion of the food. The duration of symptoms lasted from <10 minutes to > 6 hours (median 120 minutes). Among the patients the description of discomfort was often similar consisting of a tightening or pressure in the mid sternum. The most common foods inducing symptoms were beans, melon and beer. The symptoms were significant enough that patients attempted to subsequently avoid these foods. All patients were able to distinguish between symptoms related to their pollen food allergy syndrome and FIRE.The exact mechanism of this esophageal discomfort has not been elucidated. It appears distinct from pollen food allergy syndrome. It also appears different from EoE as uncommon foods such as banana, melon and avocado were capable of invoking symptoms, notably foods more commonly associated with oral allergy syndrome. However the strong association with atopy, the rapid onset of symptoms and symptoms distinct from dysphagia suggest a local possibly immunologic factor causing an immediate esophageal mucosal response. A careful history of FIRE symptoms should be part of the routine evaluation of patients with eosinophilic esophagitis. Further investigations will be required to help better understand the frequency and mechanism of this newly described phenomenon.Conflicts of InterestMH no conflicts, AS no conflictsMark Holbreich M.D.Alex Straumann M.D.1. Schoepfer AM, Straumann A, Panczak R, et al. Development and validation of a symptom-based activity index for adults with eosinophilic esophagitis. Gastroenterology 2014;147:1255–1266.2. Biedermann, L, Holbreich, M, Atkins, D, et al. Food‐induced immediate response of the esophagus—A newly identified syndrome in patients with eosinophilic esophagitis. Allergy . 2020; 00: 1– 9.Corresponding authorMark Holbreich M.D.Allergy and Asthma ConsultantsIndianapolis IN [email protected]
Following the emergency use authorization of the vaccine mRNA-1273 on 18th December 2020 in the US and the vaccine BNT162b2 one week earlier, two mRNA vaccines are in currently used for the prevention of coronavirus disease 2019 (COVID-19). Phase 3 pivotal trials on both vaccines excluded individuals with a history of allergy to vaccine components. Immediately after the initiation of vaccination in the United Kingdom, Canada, and in the US, anaphylactic reactions have been reported. While the culprit trigger requires investigation, initial reports suggested the excipient polyethylene glycol 2000 (PEG-2000), which is contained in both vaccines as PEG-micellar carrier system as the potential culprit. Surface PEG chains form a hydrate shell to increase stability and prevent opsonization. Allergic reactions to such PEG-ylated lipids are rarely IgE-mediated, but may result from complement activation-related pseudoallergy (CARPA) that has been described to similar liposomes. In addition, mRNA-1273 also contains tromethamine (trometamol), which has been reported to cause anaphylaxis to e.g. gadolinium-based or iodinated contrast media. Skin prick-, intradermal-, epicutaneous- tests, in vitro sIgE assessment, evaluation of sIgG/IgM, as well as basophil activation test are in use to demonstrate allergic reactions to various components of the vaccines.
Coronavirus disease 2019 (COVID-19) vaccine BNT162b2 received approval and within the first few days of public vaccination several severe anaphylaxis cases occurred. An investigation is taking place to understand the cases and their triggers. The vaccine will be administered to a large number of individuals worldwide and concerns raised for severe adverse events might occur. With the current information, the European Academy of Allergy and Clinical Immunology (EAACI) states its position for the following preliminary recommendations that are to be revised as soon as more data emerges. To minimize the risk of severe allergic reactions in vaccinated individuals, it is urgently required to understand the specific nature of the reported severe allergic reactions, including the background medical history of the individuals affected and the mechanisms involved. To achieve this goal all clinical and laboratory information should be collected and reported. Mild and moderate allergic patients should not be excluded from the vaccine as the exclusion of all these patients from vaccination may have a significant impact on reaching the goal of population immunity. Health care practitioners vaccinating against COVID-19 are required to be sufficiently prepared to recognise and treat anaphylaxis properly with the ability to administer adrenaline. A mandatory observation period after vaccine administration of at least 15 minutes for all individuals should be followed. The current guidelines, which exclude patients with severe allergies from vaccination with BNT162b2, should be re-evaluated after more information and experience with the new vaccine develops.
Background: Hereditary angioedema (HAE) attacks can be provoked with psychological factors. The aim of this study was to assess the effects of anxiety, depression and stress related to COVID-19 pandemic on disease activity of HAE patients during the quarantine period (QP) and the return to normal period (RTNP). Methods: This prospective study was conducted between March 2020 and September 2020 in four allergy centres. Demographic, clinical features and mental health status were evaluated in QP (from March to the beginning of June) and RTNP (from June to the beginning of September) was applied by the government. The 10-point visual analogue scale (VAS10) was used to define the severity of HAE attacks. Depression-Anxiety- Stress Scale-21 (DASS-21) and Fear of Covid-19 (FC-19) scales were performed to assess mental health status. Results: 139 HAE patients were included in the study. In QP, median attack numbers and median VAS10 scores were 5 (min-max: 0-45) and 6 (min-max: 0-10), respectively. HAE attack numbers, DASS-21 stress, anxiety, depression and total DASS-21 scores, as well as FC-19 scores were higher in QP than RTNP (p= 0.001, p <0,001, p = 0,001, p <0,001, p <0.001, p<0.001, respectively). However, there was no difference in attack severity scores between the two periods (p>0.05). Conclusions: This study revealed that the restriction measures during Covid-19 outbreak causes an increase in the number of HAE attacks in relation to anxiety, depression, stress and fear of Covid-19 pandemic. Therefore, it is important to provide psychological support to HAE patients during the pandemic.
Involvement of small airways, those of less than 2 mm in internal diameter, is present in all stages of asthma and contributes substantially to the pathophysiologic expression of asthma. Therefore, small airways are increasingly viewed as a potential target in optimal asthma control. Airway tone, which is increased in asthma, is mainly controlled by the vagus nerve that releases acetylcholine (ACh) and activates muscarinic ACh receptors (mAChRs) post-synaptically on airway smooth muscle (ASM). In small airways, M3 mAChRs are expressed, but there is no vagal innervation. Non-neuronal ACh released from the epithelial cells that may express choline acetyltransferase (ChAT) in response to inflammatory stimuli, as well as from other structural cells in the airways, including fibroblasts and mast cells, can activate these receptors. By antagonizing M3 mAChR, the contraction of the ASM is prevented and, potentially, local inflammation can be reduced and the progression of remodeling may be affected. In fact, ACh also contributes to inflammation and remodeling of the airways and regulates the growth of ASM. Several experimental studies have demonstrated the potential benefit derived from the use of mAChR antagonists, mainly long-acting mAChR antagonists (LAMAs), on small airways in asthma. However, there are several confounding factors that may cause a wrong estimation of the relationship between LAMAs and small airways in asthma.