Non-steroidal anti-inflammatory drugs (NSAIDs) and other eicosanoid pathway modifiers are among the most ubiquitously used medications in the general population. Their broad anti-inflammatory, antipyretic and analgesic effects are applied against symptoms of respiratory infections, including SARS-CoV-2, as well as in other acute and chronic inflammatory diseases that often coexist with allergy and asthma. However, the current pandemic of COVID-19 also revealed the gaps in our understanding of their mechanism of action, selectivity and interactions not only during viral infections and inflammation, but also in asthma exacerbations, uncontrolled allergic inflammation, and NSAIDs-exacerbated respiratory disease (NERD). In this context, the consensus report summarises currently available knowledge, novel discoveries and controversies regarding the use of NSAIDs in COVID-19, and the role of NSAIDs in asthma and viral asthma exacerbations. We also describe here novel mechanisms of action of leukotriene receptor antagonists (LTRAs), outline how to predict responses to LTRA therapy and discuss a potential role of LTRA therapy in COVID-19 treatment. Moreover, we discuss interactions of novel T2 biologicals and other eicosanoid pathway modifiers on the horizon, such as prostaglandin D2 antagonists and cannabinoids, with eicosanoid pathways, in context of viral infections and exacerbations of asthma and allergic diseases. Finally, we identify and summarise the major knowledge gaps and unmet needs in current eicosanoid research.
Microbial metabolism of specific dietary components, such as fiber, contribute to the sophisticated inter-kingdom dialogue in the gut that maintains a stable environment with important beneficial physiological, metabolic, and immunological effects on the host. Historical changes in fiber intake may be contributing to the increase of allergic and hypersensitivity disorders as fiber-derived metabolites are evolutionarily hardwired into the molecular circuitry governing immune cell decision making processes. In this review, we highlight the importance of fiber as a dietary ingredient, its effects on the microbiome, its effects on immune regulation, and potential mechanisms for dietary fibers in the prevention and management of allergic diseases. In addition, we review the human studies examining fiber or prebiotic interventions on asthma and respiratory outcomes, allergic rhinitis, atopic dermatitis, and overall risk of atopic disorders. While exposures, interventions and outcomes were too heterogeneous for meta-analysis, there is significant potential for using fiber in targeted manipulations of the gut microbiome and its metabolic functions in promoting immune health.
Increased circulating CRTH2+Tregs are associated with asthma control and exacerbation Short running title:Increased circulating CRTH2+Tregs among patients with asthmaTeerapol Chantveerawonga, Sasipa Sangkangjanavanicha,b, Chirawat Chiewchalermsria,c, Panitan Pradubpongsaa, Wat Mitthamsiria, Sarawut Jindaratd, Ming Wange, Mübeccel Akdisf, Milena Sokolowskaf, Cezmi A. Akdisf, Atik Sangasapaviliyaa, Tadech Boonpiyathada,faDivision of Allergy and Clinical Immunology, Department of Medicine, Phramongkutklao Hospital, Bangkok, Thailandb Division of Allergy, Immunology and Rheumatology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, ThailandcDepartment of Medicine, Panyananthaphikkhu Chonprathan Medical Center, Srinakharinwirot University, Nonthaburi, ThailanddDepartment of Pharmacology, Phramongkutklao College of Medicine, Bangkok, ThailandeDepartment of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, and the Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, ChinafSwiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, and the Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos, Switzerland
Immune modulation is a key therapeutic tool for allergic diseases and asthma. It can be achieved in an antigen-specific way via allergen immunotherapy (AIT) or in endotype-driven approach using biologicals that target the major pathways of the type 2 (T2) immune response: IgE, IL-5 and IL-4/IL-13. COVID-19 vaccine provides an excellent opportunity to tackle the global pandemics and is currently being applied in an accelerated rhythm worldwide. It works as well through immune modulation. Thus, as there is an obvious interference between these treatment modalities recommendations on how they should be applied in sequence are expected. The European Academy of Allergy and Clinical Immunology (EAACI) gathered an outstanding expert panel under its Research and Outreach Committee (ROC). This expert panel was called to evaluate the evidence and formulate recommendation on the administration of COVID-19 vaccine in patients with allergic diseases and asthma receiving AIT or biologicals. The panel also formulated recommendations for COVID-19 vaccine in association with biologicals targeting the type 1 or type 3 immune response. In formulating recommendations, the panel evaluated the mechanisms of COVID-19 infection, of COVID-19 vaccine, of AIT and of biologicals and considered the data published for other anti-infectious vaccines administered concurrently with AIT or biologicals.
Allergic diseases include asthma, atopic-dermatitis, allergic-rhinitis, drug hypersensitivity and food-allergy. During the past years, there has been a global outbreak of allergic diseases, presenting a considerable medical and socioeconomical-burden. A large fraction of allergic diseases is characterized by a type-2 immune response involving Th2 cells, type-2 innate lymphoid cells, eosinophils, mast cells, and M2 macrophages. Biomarkers are valuable parameters for precision medicine as they provide information on the disease endotypes, clusters, precision diagnoses, identification of therapeutic targets, and monitoring of treatment efficacies. The availability of powerful omics technologies, together with integrated data analysis and network-based approaches can help the identification of clinically useful biomarkers. These biomarkers need to be accurately quantified using robust and reproducible methods, such as reliable and point-of-care systems. Ideally, samples should be collected using quick, cost-efficient and non-invasive methods. In recent years, a plethora of research has been directed towards finding novel biomarkers of allergic diseases. Promising biomarkers of type-2 allergic diseases include sputum eosinophils, serum periostin and exhaled nitric-oxide. Several other biomarkers, such as pro-inflammatory mediators, miRNAs, eicosanoid molecules, epithelial barrier integrity, and microbiota changes are useful for diagnosis and monitoring of allergic diseases and can be quantified in serum, body-fluids and exhaled-air. Herein, we review recent studies on biomarkers for the diagnosis and treatment of asthma, chronic-urticaria, atopic-dermatitis, allergic-rhinitis, chronic-rhinosinusitis, food-allergies, anaphylaxis, drug hypersensitivity and allergen-immunotherapy. In addition, we discuss COVID-19 and allergic diseases within the perspective of biomarkers and recommendations on the management of allergic and asthmatic patients during the COVID-19 pandemic.
T regulatory cells from people with asthma show a Th2-like phenotypeKirstin Jansen1, Oliver F. Wirz1, Willem van de Veen1,2, Ge Tan1,3, Milena Sokolowska1, Simon D. Message4, Tatiana Kebadze4, Nicholas Glanville4, Patrick Mallia4, Cezmi A. Akdis1,2, Sebastian L. Johnston4, Kari Nadeau5 and Mübeccel Akdis1*1 Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.2 Christine Kühne – Center for Allergy Research and Education (CK-CARE), Davos, Switzerland.3 Functional Genomics Center Zürich, ETH Zürich/University of Zürich, Zürich, Switzerland.4 National Heart and Lung Institute, Imperial College London, United Kingdom.5 Sean N. Parker Center for Allergy and Asthma Research, Department of Medicine, Stanford University, Palo Alto, CA, USA.* Corresponding author:Mübeccel Akdis, MD, PhD.Swiss Institute of Allergy and Asthma Research (SIAF)Herman-Burchard-Strasse 9CH-7265 Davos-Wolfgang, SwitzerlandE-mail: email@example.comTel.: +41 81 410 08 48Declaration of fundingM. Akdis has received research support from the Swiss National Science Foundation No. 320030-159870/310030-179428 and PREDICTA (No: 260895) and the Sean N Parker Center for Allergy and Asthma Research at Stanford University. C.A. Akdis is employed by the Swiss Institute of Allergy and Asthma Research, University of Zurich; the Swiss National Science Foundation No. 310030-156823, and the Christine Kühne – Center for Allergy Research and Education (CK-CARE). M. Sokolowska received research grant from the Swiss National Science Foundation No. 310030_189334/1 and from the GSK. The experimental infection study was supported by a Medical Research Council Clinical Research Fellowship (to S.D.M.), a British Medical Association H.C. Roscoe Fellowship (to S.D.M.), British Lung Foundation/Severin Wunderman Family Foundation Lung Research Program Grant P00/2, Asthma UK Grants 02/027 and 05/067, Welcome Trust Grants 063717 and 083567/Z/07/Z for the Centre for Respiratory Infection, Imperial College, and the National Institute for Health Research (NIHR) Biomedical Research Center funding scheme. S. L. Johnston is the Asthma UK Clinical Professor (grant CH11SJ), is an NIHR Emeritus Senior Investigator and was supported by MRC Centre Grant G1000758, Asthma UK Centre Grant AUK-BC-2015-01 and European Research Council Advanced Grant 788575. K.C. Nadeau is supported by NIH grant U19 AI104209 (Asthma and Allergic Diseases Cooperative Research Center), U01 AI140498 and R01 AI140134 and the Naddisy Foundation.To the editor,Asthma is the most common chronic inflammatory disease of the lung, characterised by wheezing, shortness of breath and variable airflow obstruction. It is a heterogeneous disease that can be classified into different endotypes of which T2-high - allergic asthma is one of the most common forms, especially in children. Allergic asthma is characterised by increased IgE and type-2 cytokines, including IL-5, IL-4 and IL-131.Thus far, it is not completely understood why these type-2 responses are poorly controlled in asthma. T regulatory cells (Treg cells) are key mediators in controlling type 2 responses. However, under certain conditions, Treg cells can display a pathogenic and proinflammatory phenotype and contribute to disease pathogenesis2. Treg cells of food allergic children showed a T helper 2 (Th2)-like phenotype. Whether this Th2-like phenotype of Treg cells is also present in asthmatic individuals is unknown.Therefore, in this exploratory study, we compared the gene-expression profile of Tregs from people with stable allergic-asthma to non-allergic controls without asthma. We isolated PBMCs from 5 people with asthma and 4 controls (Table S1) and sorted Treg cells with flow cytometry (CD3+CD4+D25hiCD127low). Then, we isolated RNA from the sorted Treg cells and performed RNA-seq (See Supplemental information for detailed methods). In total, 369 genes were differentially expressed between Treg cells from asthmatic individuals and controls (P<0.01) (Supplemental Figure 1). We clustered the genes into different groups: Treg cell markers, cytokine receptors, virus related, transcription factors, cytokines and others (Figure 1A). Interestingly, we found that the expression of FOXP3was reduced in Treg cells from asthmatic individuals (Figure 1B). This is in line with a previous study that observed a lower expression ofFOXP3 in Treg cells from individuals with asthma3. Interestingly FOXP3 expression inversely correlated with the IgE levels found in the serum (Figure 2A), supporting the finding that Treg cells can suppress IgE production4.In addition, we found a significant upregulation of IL13 mRNA expression and a trend to increased expression of IL4 andIL5 mRNAs in Tregs in asthma, indicating a Th2-like phenotype as was reported in Tregs from children with food allergies2. Furthermore, we found an upregulation of the prostaglandin D2 receptor (PTGDR2 ) or CRTH2, in line with a previous study that reported an increased amount of CRTH2+ Tregs in asthma5.Interestingly, several cytokine receptors were differentially expressed between Tregs from asthmatic individuals compared to controls. The IL-4 receptor alpha transcript IL4RA was significantly reduced in asthma. The expression of IL4RA also strongly correlated with the levels of IgE in the serum (Figure 2A). Previously, it was shown in mice that IL-4 receptor signalling is essential in controlling Th2 responses and airway inflammation6. Our data suggest a similar role of IL4RA in humans. Likewise, we observed a downregulation of TNF receptor superfamily member 25 (TNFRSF25 ), which was shown to contribute to preventing allergic lung inflammation7 and downregulation of OX40 (TNFRSF4 ).Additionally, we observed a difference in virus/type-I interferon(IFN)-related genes in asthma, which was also observed in single-cell transcriptomic data of allergen-specific Tregs from individuals with asthma8. Curiously, the expression of the type 1 IFN receptors IFNAR1/2 were lower expressed in asthma, which could indicate a deficiency against respiratory viruses and chronicity.Lastly, we performed an enrichment analysis to see up or downregulation of pathway maps, process networks and go processes with MetaCore (Table 1). The pathway maps and process networks included upregulation of pathways related to immune functions already described. However, the affected GO processes were mostly related to epigenetic mechanisms including nucleosome organisation, nucleosome assembly and chromatin organisation. With the tool STRING, we performed a pathway analysis that showed a cluster of histone genes (Figure 2B). So far, there is no data reporting the function of histone genes in Tregs or related to asthma, but perhaps this finding could be related to changes in epigenetics. It was reported that in asthma Tregs have increased CpG methylation of theFOPX3 locus compared to individuals without asathma3.In conclusion, Tregs from individuals with asthma show reduced expression of several molecules related to Treg suppressive functionality, while having increased expression of Th2-like characteristics that could lead to their reduced control of allergic airway inflammation. Further studies are needed to confirm these findings in a larger population and investigate their contribution to disease pathology.References1. Kuruvilla, M. E., Lee, F. E. H. & Lee, G. B. Understanding Asthma Phenotypes, Endotypes, and Mechanisms of Disease. Clinical Reviews in Allergy and Immunology (2019). doi:10.1007/s12016-018-8712-12. Noval Rivas, M. & Chatila, T. A. Regulatory T cells in allergic diseases. Journal of Allergy and Clinical Immunology138 , 639–652 (2016).3. Runyon, R. S. et al. Asthma Discordance in Twins Is Linked to Epigenetic Modifications of T Cells. PLoS One (2012). doi:10.1371/journal.pone.00487964. Meiler, F., Klunker, S., Zimmermann, M., Akdis, C. A. & Akdis, M. Distinct regulation of IgE, IgG4 and IgA by T regulatory cells and toll-like receptors. Allergy Eur. J. Allergy Clin. Immunol.(2008). doi:10.1111/j.1398-9995.2008.01774.x5. Boonpiyathad, T. et al. Impact of high-altitude therapy on type-2 immune responses in asthma patients. Allergy Eur. J. Allergy Clin. Immunol. 75 , 84–94 (2020).6. Khumalo, J., Kirstein, F., Hadebe, S. & Brombacher, F. IL-4Rα signaling in CD4+CD25+FoxP3+ T regulatory cells restrains airway inflammation via limiting local tissue IL-33. JCI Insight (2020). doi:10.1172/jci.insight.1362067. Schreiber, T. H. et al. Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation. J. Clin. Invest.(2010). doi:10.1172/JCI429338. Seumois, G. et al. Single-cell transcriptomic analysis of allergen-specific T cells in allergy and asthma. Sci. Immunol.(2020). doi:10.1126/SCIIMMUNOL.ABA60879. Message, S. D. et al. Rhinovirus-induced lower respiratory illness is increased in asthma and related to virus load and Th1/2 cytokine and IL-10 production. Proc Natl Acad Sci U S A105 , 13562–13567 (2008).10. Dobin, A. et al. STAR: Ultrafast universal RNA-seq aligner.Bioinformatics 29 , 15–21 (2013).11. Liao, Y., Smyth, G. K. & Shi, W. The Subread aligner: Fast, accurate and scalable read mapping by seed-and-vote. Nucleic Acids Res. 41 , e108 (2013).12. Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: A Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26 , 139–140 (2009).13. Szklarczyk, D. et al. The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res 45 , D362-d368 (2017).Figure 1: Tregs from asthmatic individuals show a distinct phenotype compared to controls. (A) Genes that are significantly changed in Tregs cells from asthmatic individuals compared to controls (log 2 ratio)– clustered in the groups: Treg markers, cytokine receptors, virus related, transcription factors, cytokines and others. (B) Fragments per kilo base per million mapped reads (FPKM) values of genes of interest (FOXP3, IL13, IL5, IL4, IL4R, PTGDR2, TNFRSF25, TNFRSF4, IFNAR1, IFNAR2) of all donors. N = 4 (healthy), 5 (asthma). *** p<0.001 , ** p<0.01, * p<0.05Figure 2: Phenotype of Tregs might be associated to Treg function . (A) Correlation between expression of FOXP3 (left) and IL4RA (right) with IgE serum levels. (B) Satellite plot showing a cluster of known interactions related to nucleosome assembly. Genes higher expressed in asthmatic individuals are shown in red, and lower expression in blue.
The coronavirus disease 2019 pandemic (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an unprecedented global social and economic impact, and numerous deaths. Many risk factors have been identified in the progression of COVID-19 into a severe and critical stage, including old age, male gender, underlying comorbidities such as hypertension, diabetes, obesity, chronic lung disease, heart, liver and kidney diseases, tumors, clinically apparent immunodeficiencies, local immunodeficiencies, such as early type-I interferon secretion capacity, and pregnancy. Possible complications include acute respiratory distress syndrome, shock, disseminated coagulopathy, acute kidney injury, pulmonary embolism, and secondary bacterial pneumonia. The development of lymphopenia and eosinopenia are laboratory indicators of COVID-19. Laboratory parameters to monitor disease progression include lactate dehydrogenase, procalcitonin, high-sensitivity C-reactive protein, proinflammatory cytokines such as interleukin (IL)-6, IL-1, Krebs von den Lungen-6 (KL-6) and ferritin. The development of a cytokine storm and extensive chest computed tomography imaging patterns are indicators of a severe disease. In addition, socioeconomic status, diet, lifestyle, geographical differences, ethnicity, exposed viral load, day of initiation of treatment, and quality of health care have been reported to influence individual outcomes. In this review, we highlight the scientific evidence on the risk factors of COVID-19.
In this review, we discuss recent publications on asthma and review the studies that have reported on the different aspects of the prevalence, risk factors and prevention, mechanisms, diagnosis and treatment of asthma. Many risk and protective factors and molecular mechanisms are involved in the development of asthma. Emerging concepts and challenges in implementing the exposome paradigm and its application in allergic diseases and asthma are reviewed, including genetic and epigenetic factors, microbial dysbiosis and environmental exposure, particularly to indoor and outdoor substances. The most relevant experimental studies further advancing the understanding of molecular and immune mechanisms with potential new targets for the development of therapeutics are discussed. A reliable diagnosis of asthma, disease endotyping and monitoring its severity are of great importance in the management of asthma. Correct evaluation and management of asthma comorbidity/multimorbidity, including interaction with asthma phenotypes and its value for the precision medicine approach and validation of predictive biomarkers are further detailed. Novel approaches and strategies in asthma treatment linked to mechanisms and endotypes of asthma, particularly biologicals, are critically appraised. Finally, due to the recent pandemics and its impact on patient management, we discuss the challenges, relationships, and molecular mechanisms between asthma, allergies, SARS-CoV-2 and Covid-19.
In December 2019, China reported the first cases of the coronavirus disease 2019 (COVID-19). This disease, caused by the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), has developed into a pandemic. To date it has resulted in ~5.6 million confirmed cases and caused 353,334 related deaths worldwide. Unequivocally, the COVID-19 pandemic is the gravest health and socio-economic crisis of our time. In this context, numerous questions have emerged in demand of basic scientific information and evidence-based medical advice on SARS-CoV-2 and COVID-19. Although the majority of the patients show a very mild, self-limiting viral respiratory disease, many clinical manifestations in severe patients are unique to COVID-19, such as severe lymphopenia and eosinopenia, extensive pneumonia, a “cytokine storm” leading to acute respiratory distress syndrome, endothelitis, thrombo-embolic complications and multiorgan failure. The epidemiologic features of COVID-19 are distinctive and have changed throughout the pandemic. Vaccine and drug development studies and clinical trials are rapidly growing at an unprecedented speed. However, basic and clinical research on COVID-19-related topics should be based on more coordinated high-quality studies. This paper answers pressing questions, formulated by young clinicians and scientists, on SARS-CoV-2, COVID-19 and allergy, focusing on the following topics: virology, immunology, diagnosis, management of patients with allergic disease and asthma, treatment, clinical trials, drug discovery, vaccine development and epidemiology. Over 140 questions were answered by experts in the field providing a comprehensive and practical overview of COVID-19 and allergic disease.