Modern healthcare requires a proactive and individualized response to diseases, combining precision diagnosis and personalized treatment. Accordingly, the approach to patients with allergic diseases encompasses novel developments in the area of personalized medicine, disease phenotyping and endotyping and the development and application of reliable biomarkers. A detailed clinical history and physical examination followed by the detection of IgE immunoreactivity against specific allergens still represents the state of the art. However, nowadays, further emphasis focuses on the optimization of diagnostic and therapeutic standards and a large number of studies have been investigating the biomarkers of allergic diseases, including asthma, atopic dermatitis, allergic rhinitis, food allergy, urticaria and anaphylaxis. Various biomarkers have been developed by omics technologies, some of which lead to a better classification of the distinct phenotypes or endotypes. The introduction of biologicals to clinical practice increases the need for biomarkers for patient selection, prediction of outcomes and monitoring, to allow for an adequate choice of the duration of these costly and long-lasting therapies. Escalating healthcare costs together with questions on the efficacy of the current management of allergic diseases requires further development of a biomarker-driven approach. Here, we review biomarkers in diagnosis and treatment of asthma, atopic dermatitis, allergic rhinitis, viral infections, chronic rhinosinusitis, food allergy, drug hypersensitivity and allergen-immunotherapy with a special emphasis on specific IgE, microbiome and epithelial barrier. In addition, EAACI guidelines on biologicals are discussed within the perspective of biomarkers.
This systematic review evaluates the efficacy, safety and economic impact of dupilumabcompared to standard of care for uncontrolled moderate-to-severe atopic dermatitis (AD). Pubmed, EMBASE and Cochrane Library were searched for RCTs and health economic evaluations. Critical and important AD-related outcomes were considered. The risk of bias and the certainty of the evidence were assessed using GRADE. Seven RCTs including 1845 subjects > 12 years treated with dupilumab16 to 52 weeks were evaluated. For adultsthere is high certainty that dupilumabdecreasesSCORAD (MD -30,72; 95%CI -34,65% to -26,79%) and EASI-75 (RR 3.09; 95%CI 2.45 to 3.89), pruritus (RR 2.96; 95%CI 2.37 to 3.70), rescue medication (RR 3.46; 95%CI 2.79 to 4.30), sleep disturbance (MD -7.29; 95%CI -8.23 to -6.35), anxiety/depression (MD -3.08; 95% CI -4.41 to -1.75) and improves quality of life (MD -4.80; 95% CI -5.55 to -4.06). The efficacy for adolescents is similar. Dupilumab-related adverse events (AEs) slightly increase (low certainty). The evidence for dupilumab-related serious AE is uncertain. The incremental cost-effectiveness ratio ranged from 28,500 £ (low certainty) to 124,541 US$ (moderate certainty).More data on long term safety are needed both for children and adults, together with more efficacy data in the paediatric population.
To the Editor: Asthma is a complex and heterogeneous chronic airway inflammatory disease with the involvement of environmental factors through epigenetic mechanisms.1 Accordingly, repeated injury, repair and regeneration of the airway epithelium following exposure to environmental factors and inflammation results in histological changes and functional abnormalities in the airway mucosal epithelium, which are associated with the pathophysiology of asthma.2Epigenetics is defined by heritable changes in gene expression without changes in the DNA sequence.3 Regulation of gene expression is mediated by different mechanisms such as DNA methylation, histone modifications and RNA-associated silencing by small non-coding RNAs. CpG sites are dinucleotides consisting of guanine and cytosine concentrated in clusters referred to CpG islands found at important regulatory sites, such as promoter and enhancer regions.4 Their de novo methylation occurs in response to various cellular stressors and signals by DNA methyltransferases (DNMT3a and 3b), which add a methyl group to position 5 of cytosine residues at the CpG site. During DNA replication both of the separated strands of DNA carry one methylated cytosine to be used as a template for duplication. Daughter DNA duplex strands will thus be hemi-methylated, which is recognized by a different DNA methyltransferase isoform (DNMT1).5 Because DNA methylation is a reversible process, the DNMTs are considered as a therapeutic target. Several DNMT inhibitors have been identified recently, among the non-nucleoside inhibitors, 4-aminoquoline-based inhibitors, such as SGI-1027 showed potent inhibitory activity. SGI-1027 occupies the binding site of DNMTs resulting in the prevention of access of target DNA to the substrate binding pocket.6We have demonstrated in previous studies from our laboratory that human primary bronchial epithelial cells (HBEC) isolated from patients with asthma showed lower barrier integrity compared to controls.7 To investigate the level of global methylation in HBEC, we investigated control and asthma samples for the long interspersed nuclear element-1 (LINE-1) methylation levels (Figure 1A). HBEC from asthma patients showed a tendency for higher global methylation levels, together with higher expression of 5-methylcytosine (5-mc) in immunofluorescence staining (Figure 1B). Next, we performed methylation profiling (Illumina Infinium EPIC array) to investigate genes methylated in ALI cultures of HBEC. Interestingly, in a highly methylated group of top 100 genes, we found many genes associated with cell growth, ion transport, and cytoskeletal remodeling (Figure S1). We kept our attention on the methylated epigenetic and tight junction (TJ) genes and further focused on TJs, especially zonula occludens and claudins which showed higher methylation in contrast to occludin, which was not methylated (Figure S2). As higher methylation levels were observed in HBEC of asthmatic origin, we inhibited the DNA methyltransferase enzyme with a specific inhibitor, SGI-1027, to demonstrate the role of CpG methylation on epithelial barrier integrity. ALI cultures were treated with the DNA methyltransferase inhibitor for 72 hours. Significantly decreased expression of 5-mc was observed after 48 hours of DNA-methyltransferase inhibition, demonstrating that the methylation of 5-methylcytosine (5-mc) in bronchial epithelium was reversed (Figure 2A). This prompted us to investigate the changes triggered by the inhibitor in epithelial cells. Further experiments showed increased transepithelial electric resistance (TER) in bronchial epithelial cells, in ALI from asthmatic donors after 48 hours of DNMT inhibition (Figure 2B). The link between barrier integrity and TER results were confirmed by the significantly decreased paracellular passage of FITC-labelled 4kD dextran after inhibition of DNMTs (Figure 2C). The reconstitution of TER in asthmatic ALI was associated with decreased protein DNMT1 expression and increased ZO-1 and claudin-18 proteins (Figure 2D). We also observed increased claudin-4, but not occludin expression upon DNMT inhibition (Figure S3). Increased expression of ZO-1 with an intact and honeycomb-like structure in the immunofluorescence staining of bronchial epithelial cells confirmed the effect on protein expression of bronchial epithelial barrier in asthma donors (Figure S4).Defective epithelial barrier has been established in asthma in addition to several chronic inflammatory diseases.8 Direct targeting of the epithelial barrier leakiness for the treatments represents an important target, however so far there is no treatment possibility targeting epigenetic mechanisms. The present study demonstrates an increased global methylation level in HBEC from asthmatic individuals. CpG methylation of specific genes is essential for the defect of epithelial barrier integrity, which is reversed upon DNMT inhibition. The inversion of CpG methylation, restores leakiness in the epithelium in asthma by increasing TER, decreasing paracellular flux and improves the structure of bronchial epithelial cells by increasing the expression of TJ proteins. The better understanding of the importance of epigenetic memory in chronic tissue inflammatory diseases together with the availability of treatment modalities targeting epigenetic mechanisms and transition of these molecules into the clinical studies may lead to curative treatment of allergic and autoimmune inflammatory diseases.9Paulina Wawrzyniak1, PhD,Krzysztof Krawczyk1,3, MSc,Swati Acharya5, PhD,Ge Tan1,7, PhD,Marcin Wawrzyniak1, PhD,Emmanuel Karouzakis4, PhD,Anita Dreher, Sci. Tech.,Bogdan Jakiela2, MD, PhD,Can Altunbulakli1, PhD,Marek Sanak2, MD, PhD,Liam O‘Mahony1,6, PD, PhD,Kari Nadeau5, MD, PhD,Cezmi A. Akdis1, MD1Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland, Christine Kühne-Center for Allergy Research and Education (CK-CARE)2Department of Medicine, Jagiellonian University Medical College, Krakow, Poland3Faculty of Biology and Environmental Protection, Department of Cellular Immunology, Lodz, Poland4Department of Rheumatology, University Hospital of Zurich5Departament of Medicine, Stanford University, United States6 Department of Medicine and School of Microbiology, APC Microbiome Ireland, University College Cork, Cork, Ireland.7 Functional Genomics Center Zurich, ETH Zurich/University of ZurichCorresponding author:Paulina WawrzyniakSwiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, SwitzerlandObere Strasse 22,7270 Davos, SwitzerlandTel: +41 81 410 08 48Fax: +41 81 410 08 firstname.lastname@example.orgConflict of interest:The authors declare that they have no conflicts of interest.Founding sources:Supported by Swiss National Science Foundation grants 310030_156823, and 320030_176190.Word count: 765Keywords: asthma, tight junction, CpG methylation, DNA methyltransferases,
This systematic review evaluates the efficacyand safety of omalizumab for chronic spontaneous urticaria (CSU). Pubmed, EMBASE and Cochrane Library were searched for RCTs. Critical and important CSU-related outcomes were considered. The risk of bias and the certainty of the evidence were assessed using GRADE. Ten RCTs including 1620 subjects aged 12 to 75 years old treated with omalizumab for 16 to 40 weeks were evaluated. Omalizumab 150 mg: does not result in clinically meaningful improvement(high certainty) of the urticaria activity score (UAS)7 (mean difference (MD) -5; 95%CI -7.75 to -2.25) and the itch severity score(ISS)7 (MD -2.15; 95% CI -3.2 to -1.1); does not increase (moderate certainty) quality of life (QoL) (Dermatology Life Quality Index (DLQI); MD -2.01; 95%CI -3.22 to -0.81); decreases (moderate certainty) rescue medication use (MD -1.68; 95%CI -2.95 to -0.4). Omalizumab 300 mg:results in clinically meaningful improvements(moderate certainty)of the UAS7 (MD -11.05; 95%CI -12.87 to -9.24), theISS7 (MD -4.45; 95%CI -5.39 to -3.51), and QoL (high certainty)(DLQI; MD -4.03; 95% CI -5.56 to -2.5); decreases (moderate certainty) rescue medication use (MD -2.04; 95%CI -3.19 to -0.88) and drug-related serious AEs (RR 0.77; 95%CI 0.20 to 2.91).
Background Two studies examining the association between maternal diet inflammatory indices (DII) during pregnancy and offspring asthma and/or wheeze have shown either no effect, or increased risk. Neither study investigated a biological pathway for the association. We examined the association between maternal DII and risk of offspring asthma and/or wheeze, and sought to determine whether cord sera cytokines/chemokines might connect maternal DII with offspring risk. Methods Analysis included 1228 dyads in Healthy Start, a prospective prebirth cohort from Colorado. DII scores were computed for each mother based on repeated 24-hour dietary recalls during pregnancy. Child diagnosis of asthma and/or wheeze up to four years was obtained from electronic medical records. For a subset of participants, cord sera was analyzed for five cytokines and two chemokines. Results Unadjusted analyses showed positive association between maternal DII scores and child asthma and/or wheeze by 4 years (OR = 1.17; 95% CI: 1.07, 1.27), but the association was attenuated and no longer significant in adjusted models (OR = 1.13; 95% CI: 0.99, 1.28). There were no significant associations between cord sera cytokines/chemokines and child asthma and/or wheeze. There were no significant assocations between DII scores and any cytokine or chemokine measured. Conclusion Our study showed that the inflammatory profile of the maternal diet was not significantly associated with offspring asthma and/or wheeze or cord sera cytokines and chemokines. Although the maternal diet in pregnancy seems an obvious biological target for asthma and/or wheeze prevention, factors other than the inflammatory profile need to be investigated.
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.