Coronavirus disease 2019 (COVID-19) vaccine BNT162b2 received approval and within the first few days of public vaccination several severe anaphylaxis cases occurred. An investigation is taking place to understand the cases and their triggers. The vaccine will be administered to a large number of individuals worldwide and concerns raised for severe adverse events might occur. With the current information, the European Academy of Allergy and Clinical Immunology (EAACI) states its position for the following preliminary recommendations that are to be revised as soon as more data emerges. To minimize the risk of severe allergic reactions in vaccinated individuals, it is urgently required to understand the specific nature of the reported severe allergic reactions, including the background medical history of the individuals affected and the mechanisms involved. To achieve this goal all clinical and laboratory information should be collected and reported. Mild and moderate allergic patients should not be excluded from the vaccine as the exclusion of all these patients from vaccination may have a significant impact on reaching the goal of population immunity. Health care practitioners vaccinating against COVID-19 are required to be sufficiently prepared to recognise and treat anaphylaxis properly with the ability to administer adrenaline. A mandatory observation period after vaccine administration of at least 15 minutes for all individuals should be followed. The current guidelines, which exclude patients with severe allergies from vaccination with BNT162b2, should be re-evaluated after more information and experience with the new vaccine develops.
Treatment of Chronic Spontaneous Urticaria With Benralizumab: Report of Primary Endpoint Per Protocol Analysis, and Exploratory EndpointsStandard treatments for chronic spontaneous urticaria (CSU) including the second-generation H1-antihistamines (SGAH) are often ineffective even with four-times the FDA-recommended dose.1,2Eosinophilic infiltrates and an abundance of interleukin-5 (IL5) in CSU lesions (hives) support a role for IL5 in the pathomechanism of CSU.3 Thus, the use of biologic therapies, e.g. benralizumab targeting IL5-receptor-α, in treating SGAH-resistant CSU was hypothesized.A repeated-measures, 24-week study was designed and conducted at an urticaria clinic to determine clinical efficacy of benralizumab in CSU. Twelve SGAH-unresponsive CSU patients (3 males, 9 females; 2 blacks, 10 whites; between ages 32-65 years) having a median daily Urticaria Activity Score (UAS7)4 of 4, and pruritus severity ≥2 were enrolled. After a baseline run-in period, subjects were treated with a subcutaneous placebo dose followed by benralizumab 30mg subcutaneously every month (×3 doses) followed by two off-medication monthly-visits. Subject-reported responses to UAS7 and CU-QoL questionnaires were recorded at the monthly visits. The primary and exploratory endpoints were the change in UAS7 and Chronic Urticaria Quality-of-Life Total Score (CUQoLTS) respectively, from 4 weeks after placebo dose (visit 2) to 4 weeks after last dose of benralizumab (visit 5). Nine subjects completed the study; three withdrew after the first benralizumab dose. An intent-to-treat (ITT) analysis (n=12) of the primary endpoint has been reported previously.5Per-protocol (PP) analysis (n=9) of the primary endpoint, and PP vs. ITT of the exploratory endpoint are reported here. It was presumed that lesions were not self-limiting, and any improvement in outcomes during the study were because of intervention. Non-responders to benralizumab were identified if at any time during the 16 weeks after the first benralizumab dose there was <40% improvement in UAS7 from baseline vs. responders if UAS7 was ≤6.The average duration of urticarial symptoms was 7.0 years. Baseline UAS7 and CUQoLTS ranged between 22-42 and 36-95 respectively. Both outcomes significantly improved at visit 5 vs. visit 2 in 7 of 9 (78%) subjects completing the study. The average difference (95% CL) between visit 2 and visit 5 for UAS7, was -15.5 (-4.1, -26.8, p=0.003) and for CUQoLTS, using ITT analysis, was-13.2 (-2.4, -24.0, p=0.0005) or, using PP analysis, was -11.6 (-0.8, -22.4, p=0.03) (Figure-1 ). Five responders reported no hives/pruritus (UAS7=0) at visit 5 or 6.Between responders and non-responders, the average age (51.6 vs. 53, p=0.9) and symptom duration (5 vs. 9 years, p=0.5) did not differ significantly. However, the adjusted mean UAS7 percentage difference, adjusted for symptom duration, age, and blood eosinophils (eos%), from visit 2 till visit 5 was -84% for responders and +7.5% for non-responders, p=0.0009 (Table-1) . The average baseline UAS7 was not statistically significant (27 vs. 37.5, p=0.5) between groups however, the baseline mean difference for eos% was -6±1 (p=0.001), and for basophil% was -1.2±0.2, p=0.02), which were not observed at visit 5 (eos%: 0±1, p=0.9; basophil%: 0.2±0.2, p=0.8) (Table-1 ). Thus, clinical improvement among responders was independent of baseline disease severity. Non-responsiveness to benralizumab, measured by changes in UAS7, are likely due to other mechanistic factors unrelated to eos% which are eliminated by blocking IL-5R with benralizumab(S-Figure-1) .UAS7 and CU-QoLTS values were significantly correlated (r2=0.9, p<0.0001) (S-Table-3) . CU-QoL components that improved significantly were the pruritus/wheal scores, urticarial interference with physical activities, sleep and spare time (S-Table-4) .This study supports the use of benralizumab for treatment of SGAH-unresponsive CSU. Benralizumab-related improvements in UAS7 and CUQoLTS reported here are similar to the efficacy of omalizumab in CSU reported in a previous study (S-Table-5) .6The sustained significant improvement in urticarial lesions based on subject-reported outcomes by benralizumab warrants further investigation of underlying biologic pathways to better elucidate the role of IL-5 in CSU.
To the Editor,We appreciate the interest and comments of Soriano and Ancochea1 regarding our papers 2. Further to the suggestion that “it would be of interest to repeat their statistics conducted during the first wave of COVID-19, again with the current estimates during the ongoing second wave, or later ones”, we would like to emphasize that our geographical observation was a type of anecdotal evidence that contributed to formulating a hypothesis. In a previous paper, we found that after adjusting for potentially relevant country-level confounders, there was a negative ecological association between COVID-19 mortality and the consumption of cabbage and cucumber in European countries 3. In this study, we acknowledged that “As in any ecological study, any inference from the observed association should be made at the country level, as the possibility of ecological fallacy precludes inferences at the individual level; and that further testing in properly designed individual studies would be of interest”. Indeed, what would be useful is testing the hypothesis in robust observational studies and/or clinical trials.Regarding our observation that COVID-19 could be considered as a disease of the Anthropocene 4 , other authors have recently provided a more complete description of the links between the disruption of the natural ecosystems that characterize the Anthropocene and the occurrence of zoonosis 5 6.1. Soriano J and Ancochea J. Saved by cabbage, killed by cabbage, and COVID-19. Allergy 2020; in press.2. Bousquet J, Anto JM, Czarlewski W, et al. Cabbage and fermented vegetables: from death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19. Allergy 2020. DOI: 10.1111/all.14549.3. Fonseca S, Rivas I, Romaguera D, et al. Association between consumption of vegetables and COVID-19 mortality at a country level in Europe. MedRix 2020; 10.1101/2020.07.17.201558464. O’Callaghan C and Anto J. COVID-19: The Disease of the Anthropocene.Env Res 2020; 187: 109683.doi: 109610.101016/j.envres.102020.109683. Epub 102020 May 109615.5. Morens DM and Fauci AS. Emerging Pandemic Diseases: How We Got to COVID-19. Cell 2020; 182: 1077-1092. 2020/08/28. DOI: 10.1016/j.cell.2020.08.021.6. Roche B, Garchitorena A, Guegan JF, et al. Was the COVID-19 pandemic avoidable? A call for a ”solution-oriented” approach in pathogen evolutionary ecology to prevent future outbreaks. Ecol Lett 2020 2020/09/02. DOI: 10.1111/ele.13586.JM AntoISGlobAL, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain. IMIM (Hospital del Mar Research Institute), Barcelona, Spain. Universitat Pompeu Fabra (UPF), Barcelona, Spain. CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.J BousquetCharité, Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Comprehensive Allergy Center, Department of Dermatology and Allergy, Berlin, Germany. MACVIA-France, Montpellier, France.
Groundbreaking Discoveries in ImmunologyTitle : IgE sialylation: unravelling a key anaphylactic mediatorAuthors : Beatriz Moyaa, Chiara Tontinib and Alexandra Santosc, d, e, fa. Allergy Service. Hospital Universitario 12 de Octubre, Madrid, Spainb. Lydia Becker Institute for Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UKc. Department of Women and Children’s Health (Paediatric Allergy), School of Life Course Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UKd. Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, London, UKe. Children’s Allergy Service, Guy’s and St Thomas’ Hospital, London, UKf. Asthma UK Centre of Allergic Mechanisms of Asthma, London, UKCorrespondence to : Beatriz Moya. Allergy Service. Hospital Universitario 12 de Octubre, Madrid, SpainEmail: firstname.lastname@example.orgAbbreviations: Ig, Immunoglobulin; Fab, antigen-binding fragments; Fc, fragment crystallizable region; FcεRI, Fc epsilon receptor I; MC, mast cells.Word count: 637/1000
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
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.
The role of eosinophils in allergic inflammation is well recognized. In homeostasis these cells are found in multiple healthy tissues including the lung parenchyma, but the function of these resident eosinophils is unknown. Circulating eosinophils are easily quantifiable and have been used to define “eosinophilic phenotype”, and to select patients who are likely to respond to anti-eosinophil and anti-Th2—directed therapies. However, presence of eosinophils in circulation may not necessarily indicate that the eosinophils are key effector cells for an airway disease such as asthma and this may be reason for not all patients responding well to anti-IL5 therapies despite normalization of blood eosinophils. This pro-con commentary examines the role of enumerating circulating vs luminal (sputum) eosinophils (and their activation status) not only to initiate therapies with monoclonal antibodies, but to monitor their clinical response while on therapy.
IgE, the key molecule in atopy has been shown to bind two receptors, FcRI, the high affinity receptor and FcεRII (CD23), mostly found on B cells and that binds IgE with lower affinity. Whereas cross-linking of IgE on FcRI triggers allergic reaction, binding of IgE to CD23 is known to play an important role in both IgE synthesis and presentation. Thus, targeting IgE-immune complexes on B cells has shown to enhance antibody and T cell responses in mice and humans. However, the mechanisms that regulate the targeting of the two receptors and the respective function of the two pathways in inflammation or homeostasis are still matter of debate. Here, we discuss several mechanisms related to IgE and IgE binding to both receptors, as well as the influence of the antigen binding on different immune cells expressing the receptors. One recent paper has shown that free IgE preferentially binds to FcRI whereas IgE immune complexes (IgE-ICs) are preferentially captured by CD23. Binding of IgE-ICs to CD23 on B cells can on one hand regulate serum IgE and prevent effector cell activation and on the other hand facilitate the antigen presentation by delivering antigen to dendritic cells. The data suggest that CD23 play a multifunctional role in regulating the allergic response pathway.
Background: Breastfeeding is associated with long-term health benefits, such as a lower incidence of allergy, asthma, diabetes or celiac disease. However, little is known regarding how the maternal and neonatal immune systems interact after parturition when the neonate receives nutrition from maternal breastmilk. Methods: We undertook a comparative analysis of immune repertoire and function at birth and 3 weeks of age in a cohort of 38 term neonates born by caesarean section grouped according to feeding method (breastmilk versus formula). We used flow cytometry to study the immune phenotype in neonatal and maternal blood samples and mixed lymphocyte reactions to establish the proliferation response of neonatal versus maternal lymphocytes and vice versa. The microbiome of neonatal stool samples was also investigated using 16S rRNA sequencing. Results: We show that the proportion of regulatory T cells (Tregs) increases in this period and is nearly two-fold higher in exclusively breastfed neonates compared to those who received formula milk only. Moreover, breastfed neonates show a specific and Treg-dependent reduction in proliferative T cell responses to non-inherited maternal antigens (NIMA), associated with a reduction in inflammatory cytokine production. Conclusions: These data indicate that exposure of the neonate to maternal cells through breastfeeding acts to drive the maturation of Tregs and ‘tolerizes’ the neonate towards NIMA.
Purpose Tear fluid N-Glycome from patients affected with vernal (VKC) and atopic keratoconjunctivitis (AKC) was investigated to identify specific changes in tears and to recognize possible glyco-biomarkers. Methods The analysis of N-glycans was performed using matrix-assisted laser desorption ionization mass spectrometry on single tear samples. Tears from control normal subjects (CTRL), VKC and AKC patients were processed and treated with peptide N-glycosidase F (PNGase F) to deglycosylate N-glycoproteins. Released N-glycans were purified, permethylated and analyzed by Matrix-Assisted Laser Desorption/Ionization-Time Of Flight Mass Spectrometry and tandem Mass Spectrometry (MALDI-TOF MS and MALDI-TOF MS/MS). Results More than 150 complex N-glycans, including highly fucosylated biantennary, triantennary, tetraantennary and bisecting species, were observed in our spectra. Three distinct patterns for CTRL, VKC and AKC patients were identified in terms of relative intensities for some N-glycans structures. Major variations involved bisecting and hyperfucosylated glycoforms. The most intense ions were associated to species at m/z 1907.0 (asialo, agalacto, bisected, biantennary structure – NGA2B) in CTRL MS profiles, at m/z 2605.3 and 2966.5 in VKC, and at m/z 2792.4 in AKC corresponding to a well-known biantennary, disialylated N-glycan. Several peaks were associated to structures bearing one or two Lewis X epitopes. Structures were confirmed by MS/MS analysis. Quantitative differences among the three groups were statistically significant. Conclusions Tear MS profiles are rich in specific glycoforms, particularly those with a high fucosylation degree, indicating both core and peripheral decoration. Tear N-glycome analysis provided important information for a better comprehension of VKC and AKC alterations at the molecular level
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.
Article Type: News and Views: Groundbreaking Discoveries in ImmunologyTitle: Emollients for the prevention of atopic dermatitisAuthors: Akash Kothari1(https://orcid.org/0000-0003-1980-161X), Arielle Locke2,Thomas Eiwegger1,3,4(https://orcid.org/0000-0002-2914-7829)1Translational Medicine Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada2Department of Medicine, National University of Ireland, Galway, Ireland3Division of Immunology and Allergy, Food Allergy and Anaphylaxis Program, The Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada4Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario, CanadaCorrespondence to: Thomas Eiwegger, MD, Division of Immunology and Allergy, Food Allergy and Anaphylaxis Program, The Department of Paediatrics, Hospital for Sick Children, 555 University Ave, Toronto, Canada, E-mail: email@example.com, Tel.: +1 416-813-7654 ext. 1862Conflicts of Interest: AK and AL have nothing to disclose. TE reports to act as local PI for company sponsored trials by DBV and sub-investigator for Regeneron, holds grants from Innovation Fund Denmark, CIHR outside the submitted work. He is Co-Investigator or scientific lead in three investigator initiated oral immunotherapy trials supported by the Food Allergy and Anaphylaxis Program SickKids and serves as associate editor for Allergy. He/his lab received unconditional/in-kind contributions from Macro Array Diagnostics and an unrestricted grant from ALK. He holds advisory board roles for ALK.Financial support: This work was supported by The Hospital for Sick Children, The Food Allergy and Anaphylaxis Program at The Hospital for Sick Children, and The Dr Lorus J And Dr Margery J Milne Scholarship from Victoria University at the University of Toronto.Statement of Author Contribution: All authors critically reviewed the original articles (references 6 and 7) and wrote the News & Views: Groundbreaking discoveries in Immunology article. All authors contributed, revised, edited, and approved the final version of the manuscript as submitted and agreed to be accountable for all aspects of the work.Keywords: emollient, atopic eczema, infancyAbbreviations : food allergy, FA; filaggrin gene, FLG; atopic dermatitis, AD; transepidermal water loss, TEWL; Barrier Enhancement for Eczema Prevention, BEEP; Preventing Atopic Dermatitis and Allergies, PreventADALL
Sustained milk consumption after 2 years post-Milk Epicutaneous therapy for Eosinophilic EsophagitisJonathan M. Spergel, MD, PhD1,2; Amanda B. Muir, MD2,3; Chris A. Liacouras, MD2,3;Deirdre Burke1, CRA; Megan O. Lewis, MSN, RN, CPNP1; Terri Brown-Whitehorn, MD1,2, Antonella Cianferoni, MD, PhD1,21Division of Allergy and Immunology, The Children’s Hospital of Philadelphia, PA, USA, 2Department of Pediatrics, The Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, USA, 3Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, PA, USAAuthor contribution:JMS-study design, writing manuscript, interpreting data; ABM-writing manuscript, study visits, data interpretation; CAL-writing manuscript, study design, interpreting data; DB-writing manuscript, regulatory coordinator, coordination and collection of data, study visits; MOL-writing manuscript, collection of data, study visits; TBW-writing manuscript, collection of data and study visits, AC-interpreting data, collection of data, study visits, regulatory itemsTo the Editor:Eosinophilic Esophagitis (EoE) is an allergic disease of the esophagus without any curative therapy. Typical symptoms of EoE are feeding difficulties, vomiting, abdominal pain and dysphagia and vary by age, with a diagnosis confirmed on esophageal biopsy with> 15 eosinophils/high power field (eos/hpf).1 The two treatment options for pediatric EoE2 are: 1) topical swallowed steroids, which is effective in inducing EoE remission in 50-90% of patients, depending on the dose, formulation and medication used; 2) dietary elimination of the causative allergen/s which is effective in 50-70% of patients with selective food elimination, and 95% with elemental diets3. Cow’s milk (CM) is the most common food allergen causing disease in up to 65% of patients.4 When either treatment is discontinued, inflammation and symptoms recur.3Epicutaneous immunotherapy (EPIT) is an investigational immunotherapy using low dose allergen exposure through the skin to induce desensitization. In the randomized controlled clinical trial,Study of Efficacy and Safety of Viaskin® Milk for CM-induced EoE (SMILEE Study) , 20 pediatric participants with CM-induced EoE were randomized to receive EPIT with Viaskin® Milk (n=15) or placebo (n=5)(details in appendix). After CM-induced EoE was confirmed, EPIT therapy was applied daily for 9 months during a CM-free period, followed by CM-containing diet for 2 months (Figure 1). At 11 months, subjects completed an upper endoscopy with biopsy to evaluate tissue eosinophilia as the primary endpoint. In the pre-defined per-protocol population (7 patients-Viaskin® Milk, 2 patients- placebo), Viaskin® Milk treated subjects had a lower number of eosinophils/high power field (eos/hpf) on biopsy (25.57 ± 31.19) compared to placebo (95 ± 63.64). After the blinded phase, 19 subjects were eligible to enroll in the open-label extension (additional 11 months of therapy) and had repeat endoscopy and biopsy. At the end of the open-label phase, 6/19 subjects had < 6 eos/hpf (32% response rate); 3/19 subjects had 7-14 eos/hpf for total response rate of 47%.5As part of routine clinical care, we continue to follow all 19 subjects who completed the open-label extension (currently 2 years after the end of Viaskin® Milk therapy) to understand whether CM continued in their diet without symptoms. Four of 5 subjects who had <6 eos/hpf after milk introduction were able to continue with approximately 2 servings of CM/day without any symptoms (Table 1). One of these patients had a clinically indicated endoscopy and biopsy that had 0 eosinophils. Two subjects, who had 6-14 eos/hpf during the study, continued to tolerate CM, including one subject who continued to have 6-14 eos/hpf on repeat endoscopy. In addition, 4 subjects who had significant symptoms ingesting CM and had > 15 eos/hpf during the initial SMILEE study were able to add CM back into their diet without having symptoms, as either baked CM (n=2) or regular CM with concomitant swallowed steroids therapy (n=2).The follow-up of this pilot study for the use of EPIT for milk-induced EoE suggests that the treatment effect can persist for 2 years after stopping therapy; six out of 7 patients in the responder and partial responder groups remain completely symptom-free while consuming an average of 2 servings/day of CM. In contrast to the current therapies of diet elimination or swallowed topical steroids where symptoms return when therapy is stopped, EPIT has demonstrated a persistent effectiveness. These findings align with EPIT’s proposed mechanism of action, by directly targeting and reprogramming the immune response to allergen.3 EPIT may induce true tolerance, as is observed in murine models, where Foxp3(+) CD25(+) CD4(+) T regulatory cells are induced and can transfer tolerance.6 Further longer-term studies are needed to examine this possibility and confirm these unique findings.Reference:1. Spergel JM, Dellon ES, Liacouras CA, et al. Summary of the updated international consensus diagnostic criteria for eosinophilic esophagitis: AGREE conference. Ann Allergy Asthma Immunol.2018;121:281-284.2. Spergel JM, Brown-Whitehorn TA, Muir A, Liacouras CA. Medical algorithm: Diagnosis and treatment of eosinophilic esophagitis in children. Allergy. 2020;75:1522-1524.3. Nhu QM, Aceves SS. Medical and dietary management of eosinophilic esophagitis. Ann Allergy Asthma Immunol.2018;121:156-161.4. Kagalwalla AF, Amsden K, Shah A, et al. Cow’s milk elimination: a novel dietary approach to treat eosinophilic esophagitis.J Pediatr Gastroenterol Nutr. 2012;55:711-716.5. Spergel JM, Elci OU, Muir AB, et al. Efficacy of Epicutaneous Immunotherapy in Children With Milk-Induced Eosinophilic Esophagitis. Clin Gastroenterol Hepatol. 2020;18:328-336 e327.6. Dioszeghy V, Mondoulet L, Dhelft V, et al. The regulatory T cells induction by epicutaneous immunotherapy is sustained and mediates long-term protection from eosinophilic disorders in peanut-sensitized mice. Clin Exp Allergy. 2014;44:867-881.Sincerely,Jonathan M. Spergel, MD, PhD1,2; Amanda B. Muir, MD2,3; Chris A. Liacouras, MD2,3;Deirdre Burke1, CRA; Megan O. Lewis, MSN, RN, CPNP1; Terri Brown-Whitehorn, MD1,2, Antonella Cianferoni, MD, PhD1,21Division of Allergy and Immunology, The Children’s Hospital of Philadelphia, PA, USA, 2Department of Pediatrics, The Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, USA, 3Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, PA, USAFunding Sources: The Children’s Hospital of Philadelphia Eosinophilic Esophagitis Family FundAcknowledgements: JMS, CAL, TBW and MOL are consultants for DBV Technology.Correspondence: Jonathan M. Spergel MD, PhDThe Children’s Hospital of PhiladelphiaDivision of Allergy and ImmunologyWood Bldg 3352D3401 Civic Center Blvd,Philadelphia, PA 19104Email: firstname.lastname@example.orgPhone: 1-215-590-2549Table 1