Immunoglobulin E (IgE)-mediated allergy is the most common hypersensitivity disease affecting more than 30% of the population. In genetically-predisposed subjects exposure to minute quantities of allergens leads to the production of IgE antibodies which is termed allergic sensitization and mainly occurs in early childhood. Allergen-specific IgE then binds to the high (FcRI) and low affinity receptors (FcRII, also called CD23) for IgE on effector cells and antigen-presenting cells, respectively. Subsequent and repeated allergen exposure increases allergen-specific IgE levels and, by receptor cross-linking, triggers immediate release of inflammatory mediators from mast cells and basophils whereas IgE-facilitated allergen presentation perpetuates T cell-mediated allergic inflammation. Due to engagement of receptors which are highly selective for IgE even tiny amounts of allergens can induce massive inflammation. Naturally occurring allergen-specific IgG and IgA antibodies usually recognize different epitopes on allergens compared to IgE, and do not efficiently interfere with allergen-induced inflammation. However IgG and IgA antibodies to these important IgE epitopes can be induced by allergen-specific immunotherapy or by passive immunization. These will lead to competition with IgE for binding with the allergen and prevent allergic responses. Similarly, anti-IgE treatment does the same by preventing IgE from binding to its receptor on mastcells and basophils. Here we review the complex interplay of allergen-specific IgE, IgG and IgA and the corresponding cell receptors in allergic diseases and its relevance for diagnosis, treatment and prevention of allergy.
Increase of allergic conditions has occurred at the same pace with the Great Accleration, which stands for the rapid growth rate of human activities upon Earth from 1950s. Changes of environment and lifestyle along with escalating urbanization, are acknowledged as the main underlying causes. Secondary (tertiary) prevention for better disease control has advanced considerably with innovations for oral immunotherapy and effective treatment of inflammation with corticosteroids, calcineurin inhibitors and biologic medications. Patients are less disabled than before. However, primary prevention has remained a dilemma. Factors predicting allergy and asthma risk have proven complex: risk factors increase the risk while protective factors counteract them. Interaction of human body with environmental biodiversity with micro-organisms and biogenic compounds as well as the central role of epigenetic adaptation in immune homeostasis have given new insight. Allergic diseases are good indicators of the twisted relation to environment. In various non-communicable diseases, the protective mode of the immune system indicates low-grade inflammation without apparent cause. Giving microbes, pro- and prebiotics, has shown some promise in prevention and treatment. The real-world public health programme in Finland (2008-2018) emphasized nature relatedness and protective factors for immunological resilience, instead of avoidance. The nationwide action mitigated the allergy burden, but in the lack of controls, primary preventive effect remains to be proven. The first results of controlled biodiversity interventions are promising. In the fastly urbanizing world, new approaches are called for allergy prevention, which also has a major cost saving potential.
Background: It is unclear if asthma and its allergic phenotype are risk factors for hospitalization or severe disease from SARS-CoV-2. Methods: All patients testing positive for SARS-CoV-2 between March 1 and September 30, 2020, were retrospectively identified and characterized through electronic analysis at Stanford. A sub-cohort was followed prospectively to evaluate long-term COVID-19 symptoms. Results: 168,190 patients underwent SARS-CoV-2 testing, and 6,976 (4·15%) tested positive. In a multivariate analysis, asthma was not an independent risk factor for hospitalization (OR 1·12 [95% CI 0·86, 1·45], p=0·40). Among SARS-CoV-2 positive asthmatics, allergic asthma lowered the risk of hospitalization and had a protective effect compared to non-allergic asthma (OR 0·52 (0·28, 0·91), p=0·026); there was no association between baseline medication use as characterized by GINA and hospitalization risk. Patients with severe COVID-19 disease had lower eosinophil levels during hospitalization compared to patients with mild or asymptomatic disease, independent of asthma status (p=0.0014). In a patient sub-cohort followed longitudinally, asthmatics and non-asthmatics had similar time to resolution of COVID-19 symptoms, particularly lower respiratory symptoms. Conclusions: Asthma is not a risk factor for more severe COVID-19 disease. Allergic asthmatics were half as likely to be hospitalized with COVID-19 compared to non-allergic asthmatics. Lower levels of eosinophil counts (allergic biomarkers) were associated with more severe COVID-19 disease trajectory. Recovery was similar among asthmatics and non-asthmatics with over 50% of patients reporting ongoing lower respiratory symptoms three months post-infection.
José M. Carballido1 and Hergen Spits21Novartis Institutes for Biomedical Research, Translational Medicine, Preclinical Safety, Switzerland2Department of Experimental Immunology, UMC, University of Amsterdam, Amsterdam, The Netherlands.Jan Egbert de Vries (Figure 1) is a cosmopolitan immunologist and an enthralling mentor with a large track record of innovative achievements in the fields of allergy and immunology. Jan was born in Strijen (NL), a small town located in the Hollands Diep estuary in the South of The Netherlands. He spent his youth in the NL combining his studies with his passion for sports; he became Dutch champion in decathlon. Shortly after his PhD, and like his fellow countryman Erasmus of Rotterdam, he started a long journey that brought him to France, California, Austria and Switzerland, although never settling in any of the cities he worked. Like Erasmus, he has been since an insatiable scholar (“Non est ulla studiorum satietas ”) and an inspiring mentor for a large number of students and collaborators.Jan studied at the University of Utrecht (NL) and graduated from the University of Amsterdam (NL) with a PhD in Immunology in 1976. After his graduation, he spent two years in the lab of John Mendelsohn at the University of California, San Diego (US), as a recipient of an Eleanor Roosevelt fellowship. Thereafter, he returned to Amsterdam, where he became the Head of the Department of Immunology at the National Cancer Research Institute. His groundbreaking observations on the cytotoxic activity of T lymphocytes isolated from melanoma patients (1) motivated the search for tumor-specific antigens, which could be used for the development of cancer vaccines.In 1985, Jan took on the position of Director of Immunology at the UNICET- Laboratoires for Immunological Research in Dardilly, a small village near Lyon (FR). UNICET was part of Schering Plough and collaborated closely with the DNAX Research Institute of Molecular and Cellular Biology in Palo Alto (US). It was during that time when Jan became interested in allergy, gaining a notable reputation in the field. Jan made a key contribution to the elucidation of the mechanisms controlling human IgE and IgG4 switching (Figure 2), implicating IL-4 as a key regulator of these processes (2). These were the early days when mouse helper T (Th) cells were segregated as either Th1 or Th2 subsets, following the seminal work of Tim Mossman and Bob Coffman at DNAX. Jan’s team observed these distinct phenotypes in human lymphocyte populations isolated from healthy and atopic individuals. However, against the dogma, he also described additional cytokine production profiles aside of the canonical and mutually exclusive IFN-γ or IL-4 secreting types. Now, several decades later, we appreciate the diversity and plasticity of these Th cell responses. Three years in France seemed too long time for this Dutch globetrotter and thus, in 1988, he and his research team moved to DNAX to continue their work in allergy and extend their research to regulatory responses with human T cells. Jan joined DNAX as the Head of Human Immunology and his work was key in elucidating the biology of IL-10 and IL-13 following their DNA cloning at DNAX. He showed that IL-4 and IL-13 were the triggers for allergic diseases (3) such as asthma, rhinitis and atopic dermatitis, and that IL-10 was a major factor dampening immune responses (4). His team also cloned the signaling lymphocyte activation molecule (SLAM/CD150) (5), which gave name to a new family of immune receptors involved in lymphocyte activation. The in vitr o work was expanded to in vivoexperimentation using severe combined immunodeficient (SCID) mice that were reconstituted with human tissues and cells (SCID-hu mice). These studies supported many drug development projects aiming to interfere with allergic responses and/or prevent transplant rejection.In 1997, Jan was recruited by Novartis as Global Head autoimmune and inflammatory diseases and Head of the Novartis Research Institute (NFI, from its abbreviation in German) in Vienna (AT). Jan led the transition of NFI to the Novartis Institutes for Biomedical Research (NIBR), expanding its original focus on dermatology to autoimmunity and inflammation. Jan was the founder of the Novartis Immunology Platform, a multidisciplinary group focused on the discovery and early development of both therapeutic antibodies and low molecular weight drugs targeting immune checkpoints, cytokines and cytokine receptors, G-protein-coupled receptors and other targets controlling T cell activation and tolerance induction. In 2008, he became Head of NIBR Europe. During his time in Vienna and Basel, Jan was instrumental for the advancement of many projects, particularly the development of the sphingosine 1 phosphate receptor antagonists FTY720 (Fingolimod/Gilenya®) and BAF312 (Siponimod/Mayzent®) for multiple sclerosis and in championing the clinical testing of immunotherapeutics in psoriasis as early proof of concept, which led to the approval of the anti-IL-17A monoclonal antibody AIN457 (Secukinumab/Cosentyx®). Jan also nurtured the path to initiate antigen-specific immune tolerance projects at Novartis, enabling many collaborations with scientists outside of Novartis.Jan’s remarkable ability to identify transformative opportunities, together with the experience he gained in academic and industrial settings, facilitated his transition from the big pharma industry to biotech. In this new setting, he has been acting as CEO and Chairman of AIMM Therapeutics, Chairman of Cassiopea and CEO of Tr1X, where he is developing cell and gene therapies to cure autoimmune diseases.The authors of this short biography had the privilege of working with Jan for many years during different steps of his career. We, like many other colleagues who worked side by side with Jan, learned to appreciate Jan’s extraordinary scientific insights and people skills. We had the opportunity to witness his passion for science and to learn his innovative way to approach immunology challenges and we remain honored to count on him as a source for inspiration and as a good friend.Major contributionsDiscovery of cytotoxic tumor-specific cytotoxic T cell clones from melanoma patientsCloning of human IL-4 and IL-13 and elucidation of their roles in the regulation of IgE production by human B cellsCloning and characterization of human IL-10 and demonstration of its profound immune-suppressive effectsDevelopment of Gilenya® and Mayzent®, and of Cosentyx® for the treatment of multiple sclerosis and psoriasis, respectivelyReferences1. de Vries JE, Spits H. Cloned human cytotoxic T lymphocyte (CTL) lines reactive with autologous melanoma cells. I. In vitro generation, isolation, and analysis to phenotype and specificity. J Immunol1984;132 :510–519.2. Pène J, Rousset F, Briere F, Chrétien I, Bonnefoy JY, Spits H et al. IgE production by normal human lymphocytes is induced by interleukin 4 and suppressed by interferons gamma and alpha and prostaglandin E2.Proc Natl Acad Sci USA 1988;85 :6880–6884.3. Punnonen J, Aversa G, Cocks BG, McKenzie AN, Menon S, Zurawski G et al. Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells. Proc Natl Acad Sci USA 1993;90 :3730–3734.4. de Waal Malefyt R, Abrams J, Bennett B, Figdor CG, de Vries JE. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med1991;174 :1209–1220.5. Cocks BG, Chang C-CJ, Carballido JM, Yssel H, de Vries JE, Aversa G. A novel receptor involved in T-cell activation. Nature1995;376 :260–263.
Research data derived from observational studies are accumulating quickly in the field of allergy and immunology and a large amount of observational studies are published every year. The aim of the present study was to evaluate the adherence to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist by papers published in the three European Academy of Allergy and Clinical Immunology journals, during the period 2009-2018. To this end, we conducted a bibliographic study of up to eight randomly selected papers per year per Journal. Our literature search resulted in 223 papers. Among those, 80, 80 and 63 records were from Pediatric Allergy and Immunology, Allergy and Clinical and Translational Allergy, respectively; the latter was published only from 2011 on. Prospective, case-control, and cross-sectional designs were described in 88, 43, and 92 papers, respectively. Full reporting of all STROBE items was present in 47.4%, 45.6%, and 41.2% for the cohort, cross-sectional, and case-control studies, respectively. Generally, no time trend in adherence of reporting STROBE items was observed, apart from reporting funding, which increased from 60% in 2009/2010 to more than 90% in 2018. We identified a cluster of STROBE items with low proportions of full reporting constituted by the items on reporting study design in the title and methods, variables types along with their measurement/assessment, bias and confounding, study size, and grouping of variables. It appears that the STROBE checklist is a suitable tool in observational allergy epidemiology. However, adherence to the STROBE checklist appeared suboptimal.
Sweet syndrome induced by SARS-CoV-2 Pfizer-BioNTech mRNA vaccineAS Darrigade, MD1, H Théophile, MD2, P Sanchez-Pena, MD2, B Milpied, MD1, M Colbert4, MD, S Pedeboscq5, MD, T Pistone6, MD, ML Jullié, MD7, J Seneschal, MD, PhD1,31 : Department of Adult and Pediatric Dermatology, Bordeaux University Hospitals, France2 : Department of pharmacovigilancy, Bordeaux University Hospitals, France3 : Research Unit INSERM U10354 : Department of geriatry, Clinic Bordeaux Nord, Bordeaux, France5 : Department of pharmacology, Bordeaux University Hospitals, France6: Department of infectious disease, Bordeaux University Hospitals, France7: Department of anatomopathology, Bordeaux University Hospitals, FranceManuscript word count: 607Key words : sweet syndrome, SARS-CoV-2, Pfizer-BioNTech mRNA vaccine, delayed hypersensitivity, IDRCorresponding author: A.S. Darrigade, Dermatology Department, Saint-André Hospital, 1, rue Jean Burguet 33000 Bordeaux, FrancePhone: +33556794705Fax: +firstname.lastname@example.orgFunding source: No financial disclosuresFinancial Disclosure: No external funding for this manuscriptTo the editor,A 45-year-old woman, without any past medical history or allergy presented in our clinic with a rapid onset of diffuse skin eruptions. Five days earlier, she received the first injection of the SARS-CoV-2 Pfizer-BioNTech mRNA. Concomitantly she took 1000mg paracetamol to prevent any post-vaccination syndrome. She well tolerated the preceding vaccines (influenza every year) before this one.The eruption started 24h after vaccine injection and was composed at time of the clinical exam of erythematous infiltrated papulosis located all over the body, without face involvement (Figure 1). No other extracutaneous symptoms were noted. Blood exams showed increased blood count levels with increased neutrophils count (8.77G/l), hepatic cytolysis (AST 67UI/L and ALT 116UI/l) with high level of PCR (115mg/l). SARS-CoV-2 PCR test and serology were negative. Viral tests for EBV, CMV, parvovirus B19, and Herpes simplex/Herpes zoster showed only a slight EBV reactivation. Histopathological examination of the skin biopsy showed a hyperplastic epidermis with an edematous papillary dermis. A superficial and deep dermal perivascular, periadnexal and interstitial dense infiltrate composed of neutrophils, eosinophils and lymphocytes was also a feature. Leukocytoclastic vasculitis was also seen (Figure 2A-2B). Clinical and pathological exams were compatible with the diagnosis of SS induced by SARS-CoV-2 Pfizer-BioNTech mRNA vaccine. Systemic steroid therapy (prednisone 0.5mg/kg/d) for five days was started and led to rapid improvement of the skin condition without any recurrence after treatment discontinuation. She did not receive the second vaccine injection.Patch-tests performed (14 days after steroid treatment stop, one month after SS) on both on healed and normal skin with pur SARS-CoV-2 Pfizer-BioNTech mRNA vaccine prepared less than 4 hours before were negative (Figure 1C 2-3). Then, intradermoreaction (IDR) with vaccine diluted at 1/10 on normal skin was positive in delayed reading (Figure 1C 1). Cutaneous biopsy was realized on the positive IDR reaction, showing an abundant inflammatory infiltrate predominantly with lymphocytes (Figure 2C).Cutaneous reactions after vaccine injection are rare, and heterogenous1. They could be related to the vaccine or the adjuvant. In addition, vaccine could trigger flares of chronic inflammatory conditions as it was previously reported1. At that time, minor local side effects are reported with SARS-CoV-2 vaccines such as pain, swelling or redness; hypersensitivity reactions were anaphylactic reaction but no severe delayed hypersensitivity are reported2-3. Three cases of acute febrile neutrophilic dermatosis are reported in the international bank of WHO, one in United Kingdom, one in United States of America and our case. Under SARS-CoV-2 Pfizer-BioNTech mRNA vaccine four cases of vasculitis had been reported after injection. In France one case of relapse of neutrophilic disorder was reported one day after SARS-CoV-2 Pfizer-BioNTech mRNA vaccine. The adjuvant associated with the SARS-CoV-2 Pfizer-BioNTech mRNA vaccine is polyethylene glycol (PEG) 20003. However our patient never received infusion containing PEG or polysorbate before. Patch-tests with PEG or polysorbate alone were not performed because of the negativity of the patch-test with the SARS-CoV-2 Pfizer-BioNTech mRNA vaccine. Only 10 cases of SS induced by vaccine are published so far including: 3 with seasonal influenza, 1 with influenza A, 2 with pneumococcal, 2 tuberculosis, 2 small pox4. SS is an acute inflammatory skin disease associated with important infiltration of neutrophils. Leukocytoclastic vasculitis could be present in SS5. One case of SS in a patient receiving pneumococcal vaccine showed the presence of dermal vasculitis associated with infiltration of neutrophils6. In case of anaphylactic reaction under SARS-CoV-2 Pfizer-BioNTech mRNA vaccine, the risk of relapse with the Moderna SARS-CoV-2 mRNA vaccine or SARS-CoV-2 vaccines with an adenovirus carrier and protein subunit remains unknown3, in case of SS even more.To conclude we report the first case of SS induce by SARS-CoV-2 Pfizer-BioNTech mRNA vaccine confirmed by positive IDR.
Allergic inflammation after allergen challenge – insights from the tissueTo the Editor,Limited data exist on the infiltration of eosinophils in direct response to allergen exposure in asthmatic patients. The experimental procedure of segmental allergen provocation (SAP) in mild asthmatic subjects is an extremely valuable study tool to investigate mechanisms of bronchial asthma in patients in general and in particular for the role of eosinophils. In this procedure, BAL and bronchial mucosa can be analysed simultaneously after the induction of allergic inflammation. Older studies yielded data on different time points after the challenge with contradictory results. Eosinophils were studied in mucosa and airway lumen of mild asthmatics undergoing segmental allergen provocation1,2. Here, eosinophils and their release products were investigated in thick sections of the bronchial biopsies. Subject data, methods and detailed results are given in the supplement. All subjects showed a clear eosinophilic response in the airway lumen and mucosa 24 hours after the challenge (Figure 1, S1). The data on neutrophils were inconclusive (Figure 1, S2). There was an increase of eosinophils in the mucosa and in the BAL. In the BAL the concentrations of IL‑5 and ECP were elevated (supplement). In the mucosa ECP stained areas were found elevated as well as signs of eosinophil activation and degranulation (Figure 2). ECP staining was associated with cellular structures, small granules or dispersed over a large area beneath the epithelium. The degree of released mediators into the tissue is an important parameter investigating new drugs for asthma. In the presented study not cell associated, free ECP positive granules were seen at baseline but only to a small extent. However, after allergen challenge the ECP volume was significantly increased and only few distinct cells could be detected being positive for ECP. These results suggest that in human tissue eosinophils degranulate to a significant amount after a single allergen challenge and therefore release all their toxic content into the surrounding tissue. This is in contrast to animal models of asthma where eosinophilic degranulation after allergen challenge does not occur extensively 3,4. In the present study, subjects with a strong IL-5 reaction in BAL showed a strong eosinophilic response in the lumen. However, BAL IL-5 levels did not correlate with eosinophil numbers in the mucosa or volume of ECP positive surfaces in the mucosa (Figure S3). It is a long known fact that IL-5 levels in the BAL correlate highly with absolute numbers of eosinophils in the same compartment 5. In the present study the allergic reaction is comparable to those of other studies. The missing correlation between IL-5 in the BAL and numbers of tissue eosinophils showed that the relationship between both compartments is not as simple as assumed. Here, the data for the volume of ECP positive surfaces may give an important hint. Interestingly, the volume of ECP positive surfaces was inversely correlated with TNF-α and IL-8. TNF-α enhances migration of eosinophils from mucosa to lumen shown in an in vitro cell culture model 6. Therefore, one possible explanation is the more TNF-α is found in the BAL the less activated eosinophils are found in the mucosa. In conclusion, the findings in subjects with mild asthma are in alignment with other published results and suggest that 1) human tissue eosinophils release their granules in non-provoked state, and 2) toxic content of these cells is significantly released into the surrounding tissue after a single allergen challenge whereas the distribution and the degree of activation and degranulation of eosinophils differs widely between subjects. Many eosinophils in the airways indicate many eosinophils in the mucosa. Three-dimensional analysis in thick tissue sections using confocal microscopy is a valuable tool in the investigation of bronchial biopsies from patients suffering from bronchial asthma.(Abbreviations: BAL=bronchoalveolar lavage, ECP=eosinophilic cation protein, IL=interleukin, MBP=major basic protein, NE=neutrophilic elastase, SAP=segmental allergen provocation, TNF=tumor necrosis factor)References1. Erpenbeck VJ, Hagenberg A, Dulkys Y, et al. Natural porcine surfactant augments airway inflammation after allergen challenge in patients with asthma. Am J Respir Crit Care Med.2004;169(5):578-586.2. Schaumann F, Muller M, Braun A, et al. Endotoxin augments myeloid dendritic cell influx into the airways in patients with allergic asthma.Am J Respir Crit Care Med. 2008;177(12):1307-1313.3. Denzler KL, Borchers MT, Crosby JR, et al. Extensive eosinophil degranulation and peroxidase-mediated oxidation of airway proteins do not occur in a mouse ovalbumin-challenge model of pulmonary inflammation. J Immunol. 2001;167(3):1672-1682.4. Malm-Erjefält M, Persson CG, Erjefält JS. Degranulation status of airway tissue eosinophils in mouse models of allergic airway inflammation. Am J Respir Cell Mol Biol. 2001;24(3):352-359.5. Sur S, Kita H, Gleich GJ, Chenier TC, Hunt LW. Eosinophil recruitment is associated with IL-5, but not with RANTES, twenty-four hours after allergen challenge. J Allergy Clin Immunol. 1996;97(6):1272-1278.6. Kikuchi I, Kikuchi S, Kobayashi T, et al. Eosinophil trans-basement membrane migration induced by interleukin-8 and neutrophils. Am J Respir Cell Mol Biol. 2006;34(6):760-765.Frauke Prenzler1, Thomas Tschernig2, Katherina Sewald1,5, Tibor Z Veres1,3, Susanne Rittinghausen1, Norbert Krug1,5, Jens M. Hohlfeld1,4,5, Armin Braun1,4,51Fraunhofer Institute for Toxicology and Experimental Medicine2Institute for Cell Biology and Anatomy, Saarland University, Homburg/Saar, Germany3Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA4 Institute of Immunology, Hannover Medical School, Hannover, Germany5 Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease (BREATH) research network, Hannover, GermanyCorrespondence: Armin BraunPreclinical Pharmacology and ToxicologyFraunhofer Institute for Toxicology and Experimental Medicine (ITEM)Nikolai-Fuchs-Str. 1, 30625 Hannover, Germanyemail: email@example.comPhone: +49(0)511/5350-263Acknowledgements: We would like to thank Isabelle Bleeker for processing the biopsy samples of the classical immunohistology.Funding: Supported by Deutsche Forschungsgemeinschaft (SFB587/ B8 und B4)Conflict of Interest: None of the authors has any financial interest.Contributions: AB, JH and NK planned and conducted the study. FP, AB and TT wrote the manuscript, all other authors read, corrected and approved the manuscript. TZV, KS, SR and FP established and performed the morphology and made the evaluation of tissue data.
Concerns have been raised regarding the potential negative effects on human health of water disinfectants used in swimming-pools. Among the disinfection options, the approaches using chlorine-based products have been typically preferred. Chlorine readily reacts with natural organic matter that are introduced in the water mainly through the bathers, leading to the formation of potentially harmful chlorination by-products (CBPs). The formation of CBPs is of particular concern since they have been epidemiologically associated with the development of various clinical manifestations. The higher the concentration of these volatile CBPs in the water, the higher their concentration in the air above the pool, and different routes of exposure to chemicals in swimming-pools (water ingestion, skin absorption and inhalation) contribute to the individual exposome. CBPs may affect the respiratory and skin health of those who stay indoor for long periods, such as swimming instructors, pool staff, and competitive swimmers. Whether those who use chlorinated-pools as customers, particularly children, may also be affected has been a matter of debate. In this article, the EAACI Joint Task Force of the Working Group of Allergy, Asthma & Sports and the Interest Groupf of Environmental & Occupational Allergy discusses the current evidence regarding the health effects of both acute and chronic exposures in different populations (work-related exposures, intensive sports and recreational attendance) and identify the main recommendations and unmet needs for research in this area.
COVID-19 can present with lymphopenia and extraordinary complex multi-organ pathologies that can trigger long-term sequela. Given that inflammasome products, like caspase-1, play a role in the pathophysiology of a number of co-morbid conditions, we investigated caspases across the spectrum of COVID-19 disease. We assessed transcriptional states of multiple caspases and using flow cytometry, the expression of active caspase-1 in blood cells from COVID-19 patients in acute and convalescent stages of disease. Non-COVID-19 subjects presenting with various co-morbid conditions served as controls. Single-cell RNA-seq data of immune cells from COVID-19 patients showed a distinct caspase expression pattern in T cells, neutrophils, dendritic cells and eosinophils compared to controls. Caspase-1 was upregulated in CD4+ T-cells from hospitalized COVID-19 patients compared to unexposed controls. Post-COVID-19 patients with lingering symptoms (long-haulers) also showed up-regulated caspase-1 activity in CD4+ T-cells that ex vivo was attenuated with a select pan-caspase inhibitor. We observed elevated caspase-3/7 levels in red blood cells from COVID-19 patients compared to controls that was reduced following caspase inhibition. Our preliminary results suggest an exuberant caspase response in COVID-19 that may facilitate immune-related pathological processes leading to severe outcomes. Further clinical correlations of caspase expression in different stages of COVID-19 will be needed. Pan-caspase inhibition could emerge as a therapeutic strategy to ameliorate or prevent severe COVID-19.
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.