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January 2021

Biologicals in atopic disease in pregnancy: An EAACI position paper

Birgit Pfaller, Juan José Yepes-Nuñez, Ioana Agache, Cezmi A. Akdis, Mohammad Alsalamah, Sevim Bavbek, Apostolos Bossios, Onur Boyman, Adam Chaker, Susan Chan, Alexia Chatzipetrou, George du Toit, Marek Jutel, Paula Kauppi, Antonios Kolios, Carmen Li, Andrea Matucci, Alanna Marson, Sarah Bendien, Oscar Palomares, Barbara Rogala, Zsolt Szepfalusi, Eva Untersmayr, Alessandra Vultaggio, Thomas Eiwegger


Biologicals have transformed the management of severe disease phenotypes in asthma, atopic dermatitis, and chronic spontaneous urticaria. As a result, the number of approved biologicals for the treatment of atopic diseases is continuously increasing. Although atopic diseases are among the most common diseases in the reproductive age, investigations, and information on half-life, pharmacokinetics defining the neonatal Fc receptors (FcRn) and most important safety of biologicals in pregnancy are lacking. Given the complex sequence of immunological events that regulate conception, fetal development, and the intrauterine and postnatal maturation of the immune system, this information is of utmost importance. We conducted a systematic review on biologicals in pregnancy for indications of atopic diseases. Evidence in this field is scarce and mainly reserved to reports on the usage of omalizumab. This lack of evidence demands the establishment of a multidisciplinary approach for the management of pregnant women who receive biologicals and multicenter registries for long-term follow-up, drug trial designs suitable for women in the reproductive age, and better experimental models that represent the human situation. Due to the very long half-life of biologicals, preconception counseling and healthcare provider education are crucial to offer the best care for mother and fetus. This position paper integrates available data on safety of biologicals during pregnancy in atopic diseases via a systematic review with a detailed review on immunological considerations how inhibition of different pathways may impact pregnancy.

COVID-19–associated multisystem inflammatory syndrome in children (MIS-C): A novel disease that mimics toxic shock syndrome—the superantigen hypothesis

Magali Noval Rivas, PhD; Rebecca A. Porritt, PhD; Mary Hongying Cheng, PhD; Ivet Bahar, PhD; and Moshe Arditi, MD

Cow’s milk protein b-lactoglobulin confers resilience against allergy by targeting complexed iron into immune cells

Franziska Roth-Walter, PhD; Sheriene Moussa Afify, MD; Luis F. Pacios, PhD; Bart R. Blokhuis, Ing; Frank Redegeld, PhD; Andreas Regner, MSc; Lisa-Marie Petje, BSc; Alessandro Fiocchi, MD; Eva Untersmayr, MD; Zdenek Dvorak, PhD; Karin Hufnagl, PhD; Isabella Pali-Scholl, PhD; and Erika Jensen-Jarolim, MD


Background: Beta-lactoglobulin (BLG) is a bovine lipocalin in milk with an innate defense function. The circumstances under which BLG is associated with tolerance of or allergy to milk are not understood.

Objective: Our aims were to assess the capacity of ligand-free apoBLG versus loaded BLG (holoBLG) to protect mice against allergy by using an iron-quercetin complex as an exemplary ligand and to study the molecular mechanisms of this protection. Methods: Binding of iron-quercetin to BLG was modeled and confirmed by spectroscopy and docking calculations. Serum IgE binding to apoBLG and holoBLG in children allergic to milk and children tolerant of milk was assessed. Mice were intranasally treated with apoBLG versus holoBLG and analyzed immunologically after systemic challenge. Aryl hydrocarbon receptor (AhR) activation was evaluated with reporter cells and Cyp1A1 expression. Treated human PBMCs and human mast cells were assessed by fluorescence-activated cell sorting and degranulation, respectively.

Results: Modeling predicted masking of major IgE and T-cell epitopes of BLG by ligand binding. In line with this modeling, IgE binding in children allergic to milk was reduced toward holoBLG, which also impaired degranulation of mast cells. In mice, only treatments with holoBLG prevented allergic sensitization and anaphylaxis, while sustaining regulatory T cells. BLG facilitated quercetin-dependent AhR activation and, downstream of AhR, lung Cyp1A1 expression. HoloBLG shuttled iron into monocytic cells and impaired their antigen presentation.

Conclusion: The cargo of holoBLG is decisive in preventing allergy in vivo. BLG without cargo acted as an allergen in vivo and further primed human mast cells for degranulation in an antigen-independent fashion. Our data provide a mechanistic explanation why the same proteins can act either as tolerogens or as allergens. (J Allergy Clin Immunol 2021;147:321-34.)

Current perspective on eicosanoids in asthma and allergic diseases: EAACI Task Force consensus report, part I

Milena Sokolowska; G. Enrico Rovati; Zuzana Diamant; Eva Untersmayr; Jargen Schwarze; Zuzanna Lukasik; Florentina Sava; Alba Angelina; Oscar Palomares; Cezmi A. Akdis; Liam O’Mahony; Marek Sanak; Sven-Erik Dahlen; Grzegorz Woszczek


Eicosanoids are biologically active lipid mediators, comprising prostaglandins, leukotrienes, thromboxanes, and lipoxins, involved in several pathophysiological processes relevant to asthma, allergies, and allied diseases. Prostaglandins and leukotrienes are the most studied eicosanoids and established inducers of airway pathophysiology including bronchoconstriction and airway inflammation. Drugs inhibiting the synthesis of lipid mediators or their effects, such as leukotriene synthesis inhibitors, leukotriene receptors antagonists, and more recently prostaglandin D2 receptor antagonists, have been shown to modulate features of asthma and allergic diseases. This review, produced by an European Academy of Allergy and Clinical Immunology (EAACI) task force, highlights our current understanding of eicosanoid biology and its role in mediating human pathology, with a focus on new findings relevant for clinical practice, development of novel therapeutics, and future research opportunities.

EAACI Biologicals Guidelines—Recommendations for severe asthma

Ioana Agache; Cezmi A. Akdis; Mubeccel Akdis; Giorgio Walter Canonica; Thomas Casale; Tomas Chivato; Jonathan Corren; Derek K. Chu; Stefano Del Giacco; Thomas Eiwegger; Breda Flood; Davide Firinu; James E. Gern; Eckard Hamelmann; Nicola Hanania; Irene Hernández-Martín; Rebeca Knibb; Mika Mäkelä; Parameswaran Nair; Liam O’Mahony; Nikolaos G. Papadopoulos; Alberto Papi; Hae-Sim Park; Luis Pérez de Llano; Oliver Pfaar; Santiago Quirce; Joaquin Sastre; Mohamed Shamji; Jurgen Schwarze; Oscar Palomares; Marek Jutel


Severe asthma imposes a significant burden on patients, families and healthcare systems. Management is difficult, due to disease heterogeneity, co-morbidities, complexity in care pathways and differences between national or regional healthcare systems. Better understanding of the mechanisms has enabled a stratified approach to the management of severe asthma, supporting the use of targeted treatments with biologicals. However, there are still many issues that require further clarification. These include selection of a certain biological (as they all target overlapping disease phenotypes), the definition of response, strategies to enhance the responder rate, the duration of treatment and its regimen (in the clinic or home-based) and its costeffectiveness. The EAACI Guidelines on the use of biologicals in severe asthma follow the GRADE approach in formulating recommendations for each biological and each outcome. In addition, a management algorithm for the use of biologicals in the clinic is proposed, together with future approaches and research priorities.

EUFOREA expert board meeting on uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) and biologics: Definitions and management

Claus Bachert, MD, PhD; Joe K. Han, MD, PhD; Martin Wagenmann, MD, PhD; Werner Hosemann, MD, PhD; Stella E. Lee, MD, PhD; Vibeke Backer, MD, PhD; Joaquim Mullol, MD, PhD; Philippe Gevaert, MD, PhD; Ludger Klimek, MD, PhD; Emanuel Prokopakis, MD, PhD; Andrew Knill, MD, PhD; Carlo Cavaliere, MD, PhD; Claire Hopkins, MD, PhD; and Peter Hellings, MD, PhD


Uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) is the most bothersome phenotype of chronic rhinosinusitis; it is typically characterized by a type 2 inflammatory reaction and by comorbidities, including asthma, nonsteroidal anti-inflammatory drug–exacerbated respiratory disease, and allergies. Here, the European Forum for Research and Education in Allergy and Airway Diseases proposes structured definitions to enable communication between clinicians and provides a practical algorithm to define type 2 inflammation in CRSwNP in daily clinical practice. A rational approach for the treatment of uncontrolled severe CRSwNP is discussed; it consists of evaluating the perspective and risks of surgery and efficacy and adverse events of biologics on the basis of currently available data. Further, possible combinations of surgery and biologics are discussed, and a rationale is provided. Here, it is of importance to adequately counsel the patient about both approaches to enable a decision-making process with an informed patient. Criteria for the selection of a biologic drug are provided, as several biologics for uncontrolled severe CRSwNP will be available in many countries within a short time. Further, suggestions for monitoring of the drug effects that support recognition of responders to the therapy and, subsequently, the decision regarding continuation or discontinuation of the biologic are proposed. (J Allergy Clin Immunol 2021;147:29-36.)

Intestinal epithelial cells in tolerance and allergy to dietary antigens

Rodney D. Newberry, MD and Simon P. Hogan, PhD

Past, present, and future of allergen immunotherapy vaccines

Yulia Dorofeeva; Igor Shilovskiy; Inna Tulaeva; Margarete Focke-Tejkl; Sabine Flicker; Dmitriy Kudlay; Musa Khaitov; Antonina Karsonova; Ksenja Riabova; Alexander Karaulov; Roman Khanferyan; Winfried F. Pickl; Thomas Wekerle; Rudolf Valenta


Allergen-specific immunotherapy (AIT) is an allergen-specific form of treatment for patients suffering from immunoglobulin E (IgE)-associated allergy; the most common and important immunologically mediated hypersensitivity disease. AIT is based on the administration of the disease-causing allergen with the goal to induce a protective immunity consisting of allergen-specific blocking IgG antibodies and alterations of the cellular immune response so that the patient can tolerate allergen contact. Major advantages of AIT over all other existing treatments for allergy are that AIT induces a long-lasting protection and prevents the progression of disease to severe manifestations. AIT is cost effective because it uses the patient´s own immune system for protection and potentially can be used as a preventive treatment. However, broad application of AIT is limited by mainly technical issues such as the quality of allergen preparations and the risk of inducing side effects which results in extremely cumbersome treatment schedules reducing patient´s compliance. In this article we review progress in AIT made from its beginning and provide an overview of the state of the art, the needs for further development, and possible technical solutions available through molecular allergology. Finally, we consider visions for AIT development towards prophylactic application.

Ten Rules for Implementation of a Telemedicine Program to Care for Patients with Asthma

Yudy K. Persaud, MD, MPH and Jay M. Portnoy, MD


During the coronavirus disease 2019 (COVID-19) pandemic, the use of telemedicine changed from being an optional way to see patients to becoming a necessity. It has transformed primary, specialty, and mental health services by becoming incorporating into everyday practice. Because allergists have adapted to patient care using telemedicine, use of this technology is likely to continue after COVID-19. In the process of using telemedicine, lessons have been learned. We now offer 10 rules for creating a successful telemedicine practice while also ensuring that quality asthma care is provided.  2020 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2021;9:13-21)

The Importance of Considering Olfactory Dysfunction During the COVID-19 Pandemic and in Clinical Practice

Mauli Desai, MD and John Oppenheimer, MD


The emergence of a worldwide pandemic due to coronavirus disease 2019 (COVID-19) and frequent reports of smell loss in COVID-19einfected patients have brought new attention to this very important sense. Data are emerging that smell impairment is a prominent symptom in COVID-19 and that this coronavirus behaves differently in causing olfactory dysfunction compared with other respiratory viruses. Anosmia and hyposmia, the complete and partial loss of smell, respectively, can result from many causes, most commonly from viral infections, sinonasal disease, and head trauma. Olfactory dysfunction negatively impacts quality of life, because sense of smell is important for flavor perception and the enjoyment of food. Olfaction is also important for the detection of warning smells, such as smoke, natural gas leaks, and spoiled food. Allergists and immunologists frequently encounter anosmia and hyposmia in patients with severe chronic rhinosinusitis with nasal polyps, and will likely see more infection-induced olfactory dysfunction in the era of COVID-19. Therefore, now more than ever, it is crucial that we understand this impairment, how to evaluate and how to measure it. In this review, we offer a clinically relevant primer for the allergist and immunologist on olfactory dysfunction subtypes, exploring the pathophysiology, appropriate clinical assessment, objective smell testing, and management of this condition. We will also focus on the emerging literature on COVID-19 olfactory dysfunction, its unique features, and its important implications for this pandemic.  2020 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2021;9:7-12)

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