Title: Real-life study in non-atopic severe asthma patients achieving disease control by omalizumab treatmentTo the Editor,Severe asthma is defined as asthma requiring treatment with guidelines-suggested medications for Global Initiative for Asthma (GINA) steps 4 or 5 or systemic corticosteroids for ≥50% of the previous year to prevent it from becoming ‘uncontrolled’ or which remains ‘uncontrolled’ despite this therapy.1 Up to 34%–50% of severe asthmatic patients have non-atopic (also called non-allergic) asthma. 2 A significant proportion of these patients have severe uncontrolled asthma, which requires high doses of inhaled corticosteroids (ICS) or even oral corticosteroids (OCS).2 Until the advent of biologics, treatment options in these patients have been very limited. For many years, both the pathogenesis knowledge and the results of clinical trials supported the view that anti-IgE treatment is specifically effective in allergic asthma. Interestingly, recent molecular and clinical evidence suggests that anti-IgE treatment might also be effective in patients with non-allergic asthma.2 Omalizumab (Xolair®) is an anti-IgE monoclonal antibody that selectively binds to human IgE and prevents the binding of IgE to its receptors. Although omalizumab is indicated in Europe in patients with severe persistent allergic asthma, several case reports and short series have provided data on the value of omalizumab in patients with non-atopic asthma.3,4The observational, multicenter, retrospective, real-life FENOMA study specifically evaluated patients who achieved full asthma control after one year of treatment with omalizumab.5 The study included 345 patients, 80 (23.2%) of whom had non-atopic asthma. The present post-hoc sub-analysis aims to describe the clinical improvement of patients with non-atopic asthma. Socio-demographic and asthma-related characteristics were collected at baseline. Outcomes analyzed at baseline and after one year of treatment were those included in the definition of asthma control by GEMA guidelines.5 Medical records were reviewed between February 2015 and June 2016. For statistical comparisons, the 2-sided Wilcoxon signed-rank test was used. A P-value of <0.05 was considered to be statistically significant. All analyses were performed with the SAS statistical package (version 9.4; SAS Institute, Cary, NC).The primary outcome of this post-hoc sub-analysis was to describe the baseline characteristics and clinical improvement of non-atopic asthma patients who achieved full disease control after one-year of treatment with omalizumab through i) frequency of daytime symptoms, ii) changes in use of ICS or OCS iii) need for rescue therapy, iv) pulmonary function (forced expiratory volume in 1 second [FEV1]), v) number of non-severe exacerbations and vi) use of healthcare resources, i.e. unplanned visits to primary care or specialists and the number of days of school or workplace absenteeism due to asthma worsening. Non-severe asthma exacerbations were defined as those that did not require OCS, emergency assistance or hospitalization. Secondary outcomes include an assessment of the percentage of eosinophil blood count and exhaled nitric oxide fraction (FeNO) before and after treatment.Demographic, clinical characteristics and asthma history (before starting treatment with omalizumab) are shown in Table 1 . Mean (SD) age of patients was 58.7 (12.2) years and 65% were female. Almost all patients had daytime symptoms, 92% of patients needed rescue medication, and the mean (SD) initial dose of omalizumab was 338.7 (153.1) mg.After one year of treatment with omalizumab 50.0% (n=40) of patients had no daytime symptoms, while 37.5% (n=30) and 12.5% (n=10) had symptoms 1 and 2 days per week, respectively. Forty-one (51.2%) of the 54 patients who were receiving OCS at entry, stopped treatment (P<0.0001). Of those continuing on OCS, the average reduction of the daily dose was not statistically significant (P=0.2132). More than half of patients (53.7%, n=43) needed no rescue medication. Median FEV1 increase was 15% and there was a reduction in the number of non-severe asthma exacerbations. After one year of treatment with omalizumab, a great reduction in unplanned visits and absenteeism from school or workplace (P<0.0001; Table 2 ) was observed.Of note, the effectiveness of omalizumab was previously assessed in a Spanish multicenter registry, which evaluated 29 non-atopic severe asthma patients over 2 years.6 However, our series is the most extensive study in patients with non-atopic asthma published to date in Spain, and provides data on full disease control. There have been several potential suggestions to explain the effectiveness of omalizumab in non-atopic patients.7 In a proof-of-concept study in non-atopic asthma patients, treatment with omalizumab resulted – as per in atopic patients – in a significant reduction of high-affinity IgE receptor (FcεRI) expression on blood basophils and plasmacytoid dendritic cells (pDC2), which hampered IgE binding and the subsequent production on proinflammatory mediators.8 Additionally, omalizumab treatment was associated with an increase in FEV1 with a positive trend in some relevant clinical endpoints, such as asthma exacerbations.8 In another proof-of-concept trial, omalizumab therapy (but not placebo) reduced IgE expression and IgE sensitization of target cells within the bronchial mucosa, and increased FEV1 versus baseline despite withdrawal of conventional therapy.9 Interestingly, it has been hypothesized that patients labelled as ‘non-allergic’ might in fact have a localized allergy to an unrecognized allergen, with elevated concentrations of allergen-specific IgE antibodies in the airways.7Our study has several limitations. Its single-arm retrospective nature relies on the accuracy and completeness of the information entered into the clinical records. This has especially affected predictors of response such as FeNO and the level of eosinophils, which were not routinely assessed in the clinical practice at the time of the study. The benefits of omalizumab presented here are those observed in the population of non-atopic patients who achieved disease control after one year of treatment with omalizumab. It is unknown how many other patients classified as non-atopic in the clinical practice did not benefit from this treatment.In summary, in the population of patients with non-atopic severe asthma who achieved full disease control after one year of treatment with omalizumab, the clinical and pulmonary benefits were remarkable and similar to those described for atopic patients. A reduction in the use of healthcare resources was also documented. Large randomized controlled trials are warranted to confirm the value of omalizumab in this population of patients.

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 protected]: +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.

Medical algorithm: Treatment of Atopic Dermatitis in Early Childhood (part II)Sherief R. Janmohamed MD PhD1, Johannes Ring MD2, Lawrence F. Eichenfield MD3, Jan Gutermuth MD11Department of Dermatology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, 1090 Jette, Brussels, Belgium2Department of Dermatology and Allergology Biederstein, Technical University Munich, München, Germany3Departments of Dermatology and Pediatrics, University of California, San Diego School of Medicine and Rady Children’s Hospital, San Diego CA, USA

Food allergy is an increasingly common disease worldwide, and is thought to be driven by an uncontrolled type 2 immune response. Current knowledge about the underlying mechanisms that initiate and promote an inappropriate immune response to dietary allergens is limited. Sensitization through the skin in early life is considered to be a key event. Food allergy results from a dysregulated type 2 response to food allergens, characterized by enhanced levels of IgE, IL-4, IL-5 and IL-13 with infiltration of mast cells, eosinophils and basophils during acute reactions. Recent data implies a possible role of innate lymphoid cells (ILCs) in driving food allergy. ILCs represent a group of lymphocytes that lack specific, recombined antigen receptors. They contribute to immune responses not only through the release of cytokines and other mediators, but also by responding to cytokines produced by activated cells in their local microenvironment. Due to their localization at barrier surfaces of the airways, gut and skin, ILCs form a link between the innate and adaptive immunity. This review summarizes recent evidences on how skin and gastrointestinal mucosal immune system contribute to both homeostasis and the development of food allergy, as well as the involvement of ILCs towards inflammatory processes and regulatory mechanisms.

Background: Pruritus has been reported as an adverse drug reaction to arsenic trioxide, but the association of arsenic exposure with pruritus has not been systematically investigated. To investigate the association of arsenic exposure with pruritus, we performed observational, interventional, and Mendelian randomization studies. Methods: A cross-sectional study was conducted in Shimen, China. A Mendelian randomization study was conducted to confirm the causal relationship between susceptibility to arsenic toxicity, in terms of genetically predicted percentages of monomethylated arsenic (MMA%) and dimethylated arsenic (DMA%) in urine, and chronic pruritus in the UK Biobank participants. Then, a case-control study in Shimen participants was conducted to determine the biomarker for pruritus, and arsenite-treated mice were used to confirm the biomarker. Last, a randomized, double-blind, placebo-controlled trial was conducted to test the efficacy of naloxone, a μ-opioid receptor antagonist, in arsenic-exposed patients with pruritus in Shimen. Results: Hair arsenic showed a dose-response relationship with the intensity of itch in 1092 participants. The Mendelian randomization analysis confirmed the causal relationship in the UK Biobank participants, with odds ratios of 1.043 for MMA% and 0.904 for DMA% above versus under median. Serum β-endorphin was identified as a significant biomarker associated with the intensity of itch. Consistently, treatment with arsenite in mice upregulated the level of β-endorphin. The randomized controlled trial showed that treatment with sublingual naloxone significantly relieved the intensity of itch in arsenic-exposed participants. Conclusion: Arsenic exposure is associated with pruritus, and β-endorphin serves as a biomarker of pruritus. Naloxone relieves pruritus in patients with [arseniasis](javascript:;).

Background: Several new variants of SARS-CoV-2 have emerged since fall 2020 which have multiple mutations in the receptor binding domain (RBD) of the spike protein. It is unclear which mutations affect receptor affinity versus immune recognition. Methods: We produced RBD with single mutations (E484K, K417N or N501Y) or with all three mutations combined and tested their binding to ACE2 by biolayer interferometry (BLI). The ability of convalescent sera to recognize RBDs and block their interaction with ACE2 was tested as well. Results: We demonstrated that single mutation N501Y increased binding affinity to ACE2 but did not significantly affect its recognition by convalescent sera. In contrast, single mutation E484K had almost no impact on the binding kinetics, but essentially abolished recognition of RBD by convalescent sera. Interestingly, combining mutations E484K, K417N and N501Y resulted in a RBD with both features: enhanced receptor binding and abolished immune recognition. Conclusion: Our data demonstrate that single mutations either affect receptor affinity or immune recognition while triple mutant RBDs combine both features.

Background: Many arguments suggest that neutrophils could play a prominent role in COVID-19. However, the role of key components of neutrophil innate immunity in severe forms of COVID-19 has deserved insufficient attention. We aimed to evaluate the involvement of Neutrophil Elastase, histone-DNA, and DNases in systemic and multi-organ manifestations of COVID-19. Methods: We performed a multicenter study of markers of neutrophil innate immunity in 155 cases consecutively recruited in a screening center (ambulatory subjects), local hospitals, and two regional university hospitals. The case were evaluated according to clinical and biological markers of severity and multi-organ manifestations and compared to 35 healthy controls. Results: Blood Neutrophil Elastase, histone-DNA, myeloperoxidase-DNA and free dsDNA were dramatically increased, and DNase activity decreased by 10-fold, compared to controls. Neutrophil Elastase and histone-DNA were associated with intensive care admission, body temperature, lung damage and markers of cardiovascular outcomes, renal failure and increased IL-6, IL-8 and CXCR2. Neutrophil Elastase was an independent predictor of the computed tomography score of COVID-19 lung damage and the number of affected organs, in multivariate analyses. The increased blood concentrations of NE and neutrophil extracellular traps were related to exacerbation of neutrophil stimulation through IL8 and CXCR2 increased concentrations and increased serum DAMPs, and to impaired degradation of NETs as a consequence of the dramatic decrease of blood DNase activity. Conclusion: Our results point out the key role of neutrophil innate immunity exacerbation in COVID-19. Neutrophil Elastase and DNase could be potential biomarkers and therapeutic targets of severe systemic manifestations of COVID-19.

Reply to Morais-Almeida.To the Editor,We appreciate Dr. Morais-Almeida’s comments 1 about our Letter to the Editor, presenting additional literature about asthma prevalence in severe COVID-19 patients and highlighting data that contrasts our hypothesis that asthma, particularly type 2 asthma, may be protective against severe disease.The data that protection may be dependent on type 2 immunity is derived from the higher percentage of asthmatics being atopic2, also reflected in the series of ~2,500 patients regularly followed up in our Allergy Unit. Yu et al. 3 provided preliminary evidence about this in a single-center retrospective study, where COVID-19 atopic patients had less severe infections, milder lung damage compared to age- and gender- matched COVID-19 controls.ACE-2, the SARS-CoV-2 receptor, is linked to type 1 and 2 interferon signatures, and found to be overexpressed in type 2-low asthmatics4. Nevertheless, different outcomes in distinct asthma phenotypes still need to be addressed in COVID-19 studies.Besides Italy and China, reports from Russia 5 on ~1,300 intensive care unit patients with SARS-CoV-2 infection confirm the observation of a low prevalence of chronic lung diseases (i.e. asthma as well as COPD).Although preliminary data on the first COVID-19 cases in the US6 seem to contrast these observations, the higher prevalence of asthma in US COVID-19 hospitalised patients should be considered alongside a higher overall prevalence in these countries compared to Europe and China, as well as on the influence of other comorbidities (i.e. obesity) and host factors (i.e. age, race: 33% were non-Hispanic black patients in the study by Garg et al.) impacting COVID-19 outcomes. Another report from Sweden 7highlights the association between severe asthma and severe COVID-19.The severe asthma phenotype is often characterized by mixed granulocytic populations (neutrophilic and eosinophilic), prevalent type 1 inflammation, increased IFN-γ levels in the airways and ineffectiveness of ICS. This severe phenotype by itself, although accounting for less than 5% of asthmatic patients, would justify the CDC (and other institutions) including asthma as a risk factor for COVID-19. Data from the UK 8, apart from confirming the role of additional comorbidities, draw attention to the recent use of oral steroids, which, indeed, may be a clue for uncontrolled and/or severe asthma.Uncontrolled asthma is a risk factor for viral exacerbations and hospitalizations and we embrace the opportunity to stress the importance of optimal adherence to asthma controlling medications, regular follow-up and specialist-assessment of disease activity. Moreover, treatable comorbidities, which may impair asthma control, should always be managed. Promoting vaccination for preventable respiratory infections (i.e. Influenza and Pneumococcal pneumonia) is also advisable. Future studies may help better distinguishing the impact of different asthma phenotypes and comorbidities on COVID-19 outcome.Carli G.1, Cecchi L.1, Stebbing J.2, Parronchi P.3, Farsi A.11 SOS Allergy and Clinical Immunology, USL Toscana Centro, Prato Italy2 Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK3 Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

Background: The administration of L-glutamine (Gln) suppresses allergic airway inflammation via the rapid upregulation of MAPK phosphatase (MKP)-1, which functions as a negative regulator of inflammation by deactivating p38 and JNK mitogen-activated protein kinases (MAPKs). However, the role of endogenous Gln remains to be elucidated. Therefore, we investigated the mechanism by which endogenous Gln regulates MKP-1 induction and allergic airway inflammation in an ovalbumin-based murine asthma model. Methods: We depleted endogenous Gln levels using l-γ-glutamyl- p-nitroanilide (GPNA), an inhibitor of the Gln transporter ASCT2, and glutamine synthetase small interfering (si)RNA. Lentivirus expressing MKP-1 was injected to achieve overexpression of MKP-1. Asthmatic phenotypes were assessed using our previously developed ovalbumin-based murine model, which is suitable for examining sequential asthmatic events, including neutrophil infiltration. Gln levels were analyzed using a Gln assay kit. Results: GPNA or glutamine synthetase siRNA successfully depleted endogenous Gln levels. Importantly, homeostatic MKP-1 induction did not occur at all, which resulted in prolonged p38 MAPK and cytosolic phospholipase A 2 (cPLA 2) phosphorylation in Gln-deficient mice. Gln deficiency augmented all examined asthmatic reactions, but it exhibited a strong bias toward increasing the neutrophil count, which was not observed in MKP-1-overexpressing lungs. This neutrophilia was inhibited by a cPLA 2 inhibitor and a leukotriene B4 inhibitor, but not by dexamethasone. Conclusion: Gln deficiency leads to the impairment of MKP-1 induction and activation of p38 MAPK and cPLA 2, resulting in the augmentation of neutrophilic, more so than eosinophilic, airway inflammation.

A document by Isabella Annesi. Click on the document to view its contents.

Autoimmunity is the break of tolerance to self-antigens that leads to organ-specific or systemic diseases characterized by the presence of pathogenic autoreactive antibodies (AAb) produced by plasmablast and/or plasma cells. AAb are prevalent in the general population and not systematically associated with clinical symptoms. In contrast, in some individuals, these AAb are pathogenic and drive the development of signs and symptoms of antibody-mediated autoimmune diseases (AbAID). AAb production, isotype profiles, and glycosylations are promoted by pro-inflammatory triggers linked to genetic, environmental, and hormonal parameters. Recent evidence supports a role for pathogenic AAb of the IgE isotype in a number of AbAID. Autoreactive IgE can drive the activation of mast cells, basophils and other types of FcεRI-bearing cells and may play a role in promoting autoantibody production and other pro-inflammatory pathways. In this review, we discuss the current knowledge on the pathogenicity of autoreactive IgE in AbAID and their status as therapeutic targets. We also highlight unresolved issues including the need for assays that reproducibly quantify IgE AAbs, to validate their diagnostic and prognostic value, and to further study their pathophysiological contributions to AbAID.

A document by Xiaoting Song. Click on the document to view its contents.

Association between asthma and clinical mortality/morbidity in COVID-19 patients using clinical epidemiologic data from Korean Disease Control & PreventionHyo-Geun Choi1, Jee Hye Wee2, So Young Kim2, Joo-Hee Kim3, Hwan Il Kim3, Ji-Young Park3, Sunghoon Park3, Yong Il Hwang3, Seung Hun Jang3, and Ki-Suck Jung31 Departments of Otorhinolaryngology-Head & Neck Surgery, Hallym UniversitySacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea2 Department of Otorhinolaryngology-Head & Neck Surgery, CHA Bundang Medical Center, CHA University, Seongnam, Korea3 Division of Pulmonary, Allergy, and Critical Care Medicine, Department ofMedicine, Hallym University Sacred Heart Hospital, Hallym University Collegeof Medicine, Anyang, Korea

Asthma control, self-management and healthcare access during the COVID-19 Epidemic in BeijingChun Chang a* M.D., Linlin Zhanga*B.S., Fawu Dong a* B.S., Ying Liang a M.D., Yahong Chen a M.D., Ying Shang a B.S., Mairipaiti Abulikemua B.S., Yongchang Suna# M.D.aDepartment of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, China.#, Corresponding to Yongchang Sun:Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, China.North Garden Rd. 49.Haidian District, Beijing, 100191, ChinaTel: +86 010 139 1097 9132Fax +86 108 226 6989E-mail: [email protected]* Chun Chang, Linlin Zhang and Fawu Dong contributed equally to this work;To the Editor:The pandemic of COVID-19, caused by the pathogen SARS-CoV-2, has now spread around the globe. Social distancing and restriction measures during COVID-19 pandemic may have impacts on asthma control and management in terms of medication availability and healthcare access. International societies responded quickly by releasing guidance on the management of asthma during the COVID-19 pandemic1-4. However, these temporary guidelines were based largely on previous asthma guidelines and expert consensus, because evidence from related studies was lacking. Therefore, we investigated the status of asthma control, self-management, medications and healthcare utilization of asthma patients during the COVID-19 epidemic in Beijing, aiming to provide data for guideline recommendations on asthma managements during the emergency.Patients with asthma, selected randomly from our hospital database, were interviewed by phone call. Detailed description of items in the questionnaire is available in this article’s online supplementary material.We contacted 286 patients, of whom 178 (62.2%) responded with valid results. Sociodemographic data and clinical characteristics of the patients before the COVID-19 pandemic are provided as online supplements. During the COVID-19 epidemic in Beijing (January 25, 2020 to April 25, 2020), the majority (74.2%, 132/178) of the patients felt that their symptoms had not changed as compared with usual times, while 18.0% (32/178) felt better, and 7.9% (14/178) felt worse. The mean ACT score of the 178 patients was 22.76 ± 3.06 (ranging from 8 to 25) in the last 4 weeks before the survey. According to the criteria of ACT scoring from GINA, asthma was classified as well-controlled in 89.3%, not well-controlled in 6.2%, and very poorly controlled in 4.5% of the patients. During this period, only 24.7% (44/178) of the patients had ever visited a hospital or clinic for asthma, of whom 11 patients had 2 visits, and 6 had ≥3 visits, totaling 74 visits. 14.9% (11/74) of all medical visits were due to exacerbation of asthma, while the remaining visits (63/74, 85.1%) were for regular prescription of asthma medications. Only 6 patients (3.4%) sought consultation online. (Table 1)Notably, 25.6% (45/176) of the patients experienced aggravation of asthma symptoms during the COVID-19 epidemic, but 75.6% (34/45) of them did not see a doctor, because 67.6% (23/34) of the patients thought that they did not need to go to the hospital and took more medications by themselves, and the remaining 32.4% (11/34) worried about cross-infection of COVID-19 in the hospital. No patient said that they did not see a doctor because they could not arrange an appointment. Eleven patients went to the hospital due to aggravation, 81.8% (9/11) to the outpatient, while only 18.2% (2/11) to the Emergency Department (ED).Table 1 Asthma control and management during the COVID-19 epidemic in Beijing

In past ten years, microRNAs (miRNAs) have gained scientific attention due to their importance in the pathophysiology of allergic diseases and their potential as biomarkers in liquid biopsies. They act as master post-transcriptional regulators that control most cellular processes. As one miRNA can target several mRNAs, often within the same pathway, dysregulated expression of miRNAs may alter particular cellular responses and contribute or lead to the development of various diseases. In this review, we give an overview of the current research on miRNAs in allergic diseases, including atopic dermatitis, allergic rhinitis and asthma. Specifically, we discuss how individual miRNAs function in the regulation of immune responses in epithelial cells and specialized immune cells in response to different environmental factors and respiratory viruses. In addition, we review insights obtained from experiments with murine models of allergic airway and skin inflammation and offer an overview of studies focusing on miRNA discovery using profiling techniques and bioinformatic modelling of the network effect of multiple miRNAs. In conclusion, we highlight the importance of research into miRNA function in allergy and asthma to improve our knowledge of the molecular mechanisms involved in the pathogenesis of this heterogeneous group of diseases.

Background The prevalence of allergy to cat is expanding worldwide. Allergen-specific immunotherapy (AIT) has advantages over symptomatic pharmacotherapy and promises long lasting disease control in allergic patients. However, there is still a need to improve cat AIT regarding efficacy, safety and adherence to the treatment. Here we aim to boost immune tolerance to the major cat allergen Fel d 1 by increasing the anti-inflammatory activity of AIT with the established immunomodulatory adjuvant CpG, but at a higher dose than previously used in AIT. Methods Together with CpG, we used endotoxin-free Fel d 1 as therapeutic allergen throughout the study in a BALB/c model of allergy to Fel d 1, thus mimicking the conditions of human AIT trials. Multidimensional immune phenotyping including mass cytometry was applied to analyze AIT-specific immune signatures. Results We show that AIT with high-dose CpG in combination with endotoxin-free Fel d 1 reverts all major hallmarks of allergy. High dimensional CyTOF analysis of the immune cell signatures initiating and sustaining the AIT effect indicates the simultaneous engagement of both, the pDC-Treg and -B cell axis, with the emergence of a systemic GATA3+ FoxP3hi biTreg population. The regulatory immune signature also suggests the involvement of the anti-inflammatory TNF/TNFR2 signaling cascade in NK and B cells at an early stage and in Tregs later during AIT. Conclusion Our results highlight the potential of CpG adjuvant in a novel formulation to be further exploited for inducing allergen-specific tolerance in patients with cat allergy or other allergic diseases in the future.

While both the incidence and general awareness of food allergies is increasing, the variety and clinical availability of therapeutics remain limited. Therefore, investigations into the potential factors contributing to the development of food allergy and the mechanisms of natural tolerance or induced desensitization are required. In addition, a detailed understanding of the pathophysiology of food allergies is needed to generate compelling, enduring, and safe treatment options. New findings regarding the contribution of barrier function, the effect of emollient interventions, mechanisms of allergen recognition, and the contributions of specific immune cell subsets through rodent models and human clinical studies provide novel insights. With the first approved treatment for peanut allergy, the clinical management of food allergy is evolving towards less intensive, alternative approaches involving fixed doses, lower maintenance dose targets, co-administration of biologicals, adjuvants, and tolerance-inducing formulations. The ultimate goal is to improve immunotherapy and develop precision-based medicine via risk phenotyping allowing optimal treatment for each food-allergic patient.

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