key: cord-0865015-cco2vh0f authors: Vultaggio, Alessandra; Agache, Ioana; Akdis, Cezmi A.; Akdis, Mubeccel; Bavbek, Sevim; Bossios, Apostolos; Bousquet, Jean; Boyman, Onur; Chaker, Adam M.; Chan, Susan; Chatzipetrou, Alexia; Feleszko, Wojciech; Firinu, Davide; Jutel, Marek; Kauppi, Paula; Klimek, Ludger; Kolios, Antonios; Kothari, Akash; Kowalski, Marek L.; Matucci, Andrea; Palomares, Oscar; Pfaar, Oliver; Rogala, Barbara; Untersmayr, Eva; Eiwegger, Thomas title: Considerations on Biologicals for Patients with allergic disease in times of the COVID‐19 pandemic: an EAACI Statement date: 2020-06-05 journal: Allergy DOI: 10.1111/all.14407 sha: e324e1ab3ad17d8c71fa83e1320223490da44f88 doc_id: 865015 cord_uid: cco2vh0f The outbreak of the SARS‐CoV‐2‐induced Coronavirus Disease 2019 (COVID‐19) pandemic re‐shaped doctor‐patient interaction and challenged capacities of healthcare systems. It created many issues around the optimal and safest way to treat complex patients with severe allergic disease. A significant numberof the patients are on treatment with biologicals and clinicians face the challenge to provide optimal care during the pandemic. Uncertainty of the potential risks for these patients is related to the fact that the exact sequence of immunological events during SARS‐CoV‐2 is not known. Severe COVID‐19 patients may experience a “cytokine storm” and associated organ damage characterized by an exaggerated release of proinflammatory type 1 and type 3 cytokines. These inflammatory responses are potentially counteracted by anti‐inflammatory cytokines and type 2 responses. This expert based EAACI statement aims to provide guidance on the application of biologicals targeting type 2 inflammation in patients with allergic disease. Currently, there is very little evidence for an enhanced risk of patients with allergic diseases to develop severe COVID‐19 with studies focusing on severe allergic phenotypes lacking. At present, non‐infected patients on biologicals for the treatment of asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps or chronic spontaneous urticaria should continue their biologicals targeting type 2 inflammation via self‐application. In case of an active SARS‐CoV‐2 infection, biological treatment needs to be stopped until clinical recovery and SARS‐CoV‐2 negativity is established and treatment with biologicals should be re‐initiated. Maintenance of add‐on therapy and a constant assessment of disease control, apart from acute management is demanded. The outbreak leading to the pandemic of SARS-CoV-2-induced Coronavirus Disease 2019 has pushed health care systemsto the limits of their capacity across the globe. This infection can cause severe respiratory illness and multi-organ failure with clinical presentations greatly resembling SARS-CoV-1 and MERS-CoV, resulting in intensive care unit (ICU) admission and high mortality. We discuss immunological and clinical considerations for patients on biologic agents (biologicals)targeting the type 2 inflammatory response due to difficult-to-treat allergic diseases in the context of COVID-19. Both innate and adaptive immune responses participate in anti-viral immunity. The interactions between SARS-CoV-2 and both arms of the immune system have been poorly clarified until now, particularly in the view of asymptomatic individuals, patients with mild disease, and those who fully recover. Natural killer cells are involved in control of the acute phase of the viral infection, whereas CD8+ T cells are the key player in the following steps. 1 Antibody-secreting cells and T follicular helper cells are instrumental in the production of specific anti-viral IgA, IgM and IgG antibodies early on. [2] [3] [4] Antibody-dependent macrophage activation as well as lymphocyte and macrophage pyroptosis (an excessive form of inflammatory cell apoptosis) might occur and contribute to more severe tissue damage, as described in SARS-CoV infection. [5] [6] [7] [8] Among mediators, type I interferons (type I IFN) play a central role. In other coronavirus infections such as severe acute respiratory syndrome (SARS), type I IFN are critical for the initiation of immune response and virus clearance. Delayed production of type I IFN and aninsufficient cytotoxic responseis associated with a more severe clinical disease. Observations from SARS or Middle East respiratory syndrome (MERS) 5, 8 and, more recently, COVID-19 patients 9 suggest an overshooting immune response in severe cases with wide-spread lung damage and disease aggravation around 7-14 days after onset. Those severe COVID-19 patients may also experiencea picture of a so-called "cytokine storm" and associated organ damage, particularly acute respiratory distress syndrome, acute kidney and liver failure, myocarditis and disseminated vascular coagulation. These manifestations are characterized byan exaggerated release of proinflammatory This article is protected by copyright. All rights reserved cytokines, such as IL-1, IL-6, IL-8, TNF- and many more ( Figure 1 ).Consequently, these highly increased proinflammatory cytokines are believed to be potential targets for biological therapy.These type 1 and type 3-driven inflammatory responses are counteracted by antiinflammatory cytokines,such as IL-10 and TGF-, as well as potentially type 2 responses. Moreover, eosinophils have been reported to play a role in virus response. 10 Lower eosinophil counts were reported in association with severe cases, while an elevated eosinophil count was associated with a better prognosis 9 although no functional relationship has been established so far and this finding may be an epiphenomenon. Thus, probably all shades of cytokine responses (type 1 and type 3, type 2, and regulatory cytokines) are required in the healing of SARS-CoV-2 infection. An appropriate induction and downregulation of individual response batteries is necessary to achieve an efficient viral clearance, an avoidance of excessive inflammatory reaction and irreversible tissue damage ( Figure 2 ). In line with a paucity of mechanistic data on COVID-19 in the context of type 2 inflammation, knowledge on the disease course in patients treated with biologicals targeting type 2 inflammation due to severe asthma or other atopic diseases, such as CSU, AD and CRSwNP, is scarce to absent. To our knowledge by April 12 th 2020, only 6 studies presented disease characteristics of SARS-CoV-2 infection on patients with allergy or atopic diseases as a co-morbidity (Table 1) . While, in a study including 1591 patients infected with SARS-CoV-2 and admitted to ICUs of Lombardy, Italy, asthma was not referred to as a specific comorbidity and grouped under "others". 11 Allergic disease seemed to have no influence on presented symptoms and the course of the disease. [12] [13] [14] [15] None of these patients were on biologicals to treat their pre-existing allergic disease. In a recent report from the COVID-19-Associated Hospitalization Surveillance Network based on data from 14 US states from March 1 st -30 th 2020 17% of hospitalized COVID19 patients had asthma as a comorbidity. The highest percentage was in the 18-49 years old patient group with 27.3% asthmatics. No information on severity of the disease and therapy has been provided. This supports the importance of a prospective assessment of atopic diseases in the context of COVID19. This article is protected by copyright. All rights reserved In the past years, new biological therapies for severe asthma, atopic dermatitis (AD), chronicrhinosinusitis with nasal polyps (CRSwNP) and chronic spontaneous urticaria (CSU) have been developed targeting different aspects of the type 2 immune response. [16] [17] [18] [19] [20] [21] [22] [23] [24] Anti-IL-5 monoclonal antibodies (mepolizumab and reslizumab) are approved for severe asthma with peripheral eosinophilia, uncontrolled under high intensity treatment. Benralizumab, a monoclonal antibody that binds to the α subunit of IL-5 receptor (IL-5Rα) 25 was also recently approved for uncontrolled eosinophilic severe asthma. Dupilumab, a monoclonal antibody directed against the α subunit of the IL-4 receptor (IL-4Rα) acting as a dual antagonist of both IL-4 and IL-13 was approved for uncontrolled severe type 2 asthma, moderate to severe AD and CRSwNP. Omalizumab, a humanized monoclonal anti-IgE antibody, has also been approved for IgEmediated persistent allergic asthma and CSU. The low number of reports of patients on biologicals targeting type 2 disease is encouraging since type 2 diseases may predispose patients to viral infections due to compromised barriers. [26] [27] [28] [29] [30] Consequently, epidemiologic evidence closely links virus infections to both development and exacerbation of allergic diseases. [31] [32] [33] The infection and persistence of respiratory viruses is attributed to impaired innate immune responses and a predisposition to mount strong type 2 immune responses. In line with this argumentation some of these drugs provided evidence for a This article is protected by copyright. All rights reserved reduction of viral infections in asthmatics such as anti-IgE treatment with omalizumab. Itmay cause anti-inflammatory and immunomodulatory effects by restoring the capacity of human plasmacytoid dendritic cells (pDCs) to produce IFN-α, increasing antiviral activity and reducing viral-induced asthma exacerbations 31, 34 .In severe asthma, clinical trials showed that rates of respiratory infections (upper respiratory tract infection, viral upper respiratory tract infection, influenza) were lower or similar in the anti-IL-5 monoclonal antibody (mAb)-and dupilumabtreated groups compared to placebo ( Table 2) . No data are available on the impact of anti-IL-5 mAb and dupilumabon virus-induced exacerbations and antiviral responses.For dupilumab, anincreased risk of herpes-virus reactivation has been reported in real-life uncontrolled studies and case reports. The pathogenesis of cytokine storm-related tissue injury has been repeatedly reported in COVID-19, dominated by proinflammatory type 1 and type 3 associated cytokines and linked inflammasome activationand neutrophilia. It has been reported that type 2 response and Treg response can antagonize these effects and may be beneficial. 35 In this context, the inhibition of type 2 response in severe and critical COVID-19 cases may cause an aggravation of the disease. Therefore, such biologicals should be discontinued in very severe disease. Due to their long in vivo half-life in the range of a few weeks, it remains unclear to which extent such an action would impact the acute management and what the risk of losing disease control and co-morbidity later on could be. Recent systematic reviews on approved biologicals in severe asthma showed that biologicals targeting IL-5-signalling pathway (mepolizumab, reslizumab and benralizumab) slightly increase drug-related adverse events (AE) in severe eosinophilic asthma. 36 For anti-IgE (omalizumab) and anti-IL-4Rα (dupilumab) treatments rate ratios were rather small. 36 Benralizumab and omalizumab showed an increase in AEs with low to moderate certainty in severe allergic asthma. 37 There was an increased rate of dupilumab-related AEs (low certainty) in severe asthma. 38 Data from clinical trials demonstrated good safety profiles of biologicals with regards to viral infections of the upper respiratory tract ( Table 2) . [36] [37] [38] Practical and clinical recommendations Time restrictions did not allow for official guidelines to be published so far. However, several societies issued statements on the use of biologicals during the COVID-19 pandemic (Table 3) . A consensus-based ad-hoc expert panel of allergy/immunology specialists from the US and Canada This article is protected by copyright. All rights reserved recommends continuing administration of biologicals in patients with proven efficacy and converting the patient to a prefilled syringe for potential home administration if this is available or otherwise in-office application can occur with a plan to transition to home administration. 39 Initiation of biologic therapy for AD should be weighed very carefully, but it remains a viable option as this is administered at home. In a recent communication, the European Task Force on Atopic Dermatitis (ETFAD) suggested that targeted treatment selectively interfering with type 2 inflammation, such as dupilumab, is not considered to increase the risk for viral infections and might thus be preferred compared to immunosuppressive treatments such as cyclosporine in a situation such as the COVID-19 pandemic, although stressing that this theoretical advantage is not supported by robust clinical data. 40 This article is protected by copyright. All rights reserved In case of hospital admission for moderate, severe or critical SARS-CoV-2 infection,management of the allergic disease should be in accordance with current guidelinesby involving the respective subspecialties. In particular for asthma inhalation therapy use preferably metered dose inhalations with chambers that are not to be shared and pulmonary function tests should be performed only if highly necessary (Figure 3 ). Once resolution/recovery of the disease is established (e.g. via a negative SARS-CoV-2 test)but no shorter than 2 weeks post onset of the disease/positive testing, the re-administration of the biological should be re-initiated ( Figure 3 ). In conclusion, current evidence does not suggest a higher risk for severe COVID-19 in allergic individuals but data that allows estimating the risk of severe allergic phenotypes in case of SARS-CoV-2 infection is missing. Treatment of patients on biologicals targeting type 2 inflammation in allergic disease should be maintained in non-infectedindividuals. In case of an infection withholding the treatment is recommended until recovery. Additional data on those patients with more severe phenotypes will provide more insight to define more precisely the risk profile of individuals with allergic disease who are of elevated risk.The collection of such data is imperative for future data-informed adaptations of these guidelines. This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved Non-infectedpatients on biologicals for the treatment of asthma, AD, CRSwNP or CSU should continue their biologicalstargeting type 2 inflammation via self-application. In case of an active SARS-CoV-2 infection and moderate-to-severe COVID-19,biological treatment needs to be stopped until clinical recovery and SARS-CoV-2 negativity is established. Thereafter treatment with biologicals can be re-initiated. This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved According to WHO patients with chronic lung disease (e.g. such as asthma) may be prone to more severe disease. Innate and adaptive immune responses to viral infection and vaccination Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19 Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19) Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology Severe Acute Respiratory Syndrome Coronavirus Viroporin 3a Activates the NLRP3 Inflammasome Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection Immunological responses against SARS-coronavirus infection in humans Clinical features of patients infected with 2019 novel coronavirus in Wuhan Eosinophils capture viruses, a capacity that is defective in asthma Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region Covid-19 in Critically Ill Patients in the Seattle Region -Case Series Eleven Faces of Coronavirus Disease Clinical Features of 69 Cases with Coronavirus Disease Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan Precision medicine and phenotypes, endotypes, genotypes, regiotypes, and theratypes of allergic diseases EAACI IG Biologicals task force paper on the use of biologic agents in allergic disorders Future research trends in understanding the mechanisms underlying allergic diseases for improved patient care Biologicals in allergic diseases and asthma: Toward personalized medicine and precision health: Highlights of the 3rd EAACI Master Class on Biologicals Biologicals in atopic disease in pregnancy: an EAACI position paper New biological treatments for asthma and skin allergies The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria EUFOREA consensus on biologics for CRSwNP with or without asthma Dupilumab reduces local type 2 pro-inflammatory biomarkers in chronic rhinosinusitis with nasal polyposis Immunological and hematological effects of IL-5(Ralpha)-targeted therapy: An overview Targeting Antiviral Pathways for Treatment of Allergic Diseases Defective epithelial barrier in chronic rhinosinusitis: the regulation of tight junctions by IFN-gamma and IL-4 The IL-13/periostin/IL-24 pathway causes epidermal barrier dysfunction in allergic skin inflammation Nasal epithelial barrier dysfunction increases sensitization and mast cell degranulation in the absence of allergic inflammation Tight junction, mucin, and inflammasome-related molecules are differentially expressed in eosinophilic, mixed, and neutrophilic experimental asthma in mice Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children Viral infections in allergy and immunology: How allergic inflammation influences viral infections and illness Bronchiolitis needs a revisit: Distinguishing between virus entities and their treatments Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations Insights into the immuno-pathogenesis of acute respiratory distress syndrome Efficacy and safety of treatment with biologicals (benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab) for severe eosinophilic asthma Efficacy and safety of treatment with biologicals (benralizumab, dupilumab and omalizumab) for severe allergic asthma Efficacy and safety of treatment with dupilumab for severe asthma: A systematic review of the EAACI guidelines-Recommendations on the use of biologicals in severe asthma COVID-19: Pandemic Contingency Planning for the Allergy and Immunology Clinic European Task Force on Atopic Dermatitis (ETFAD) statement on severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-infection and atopic dermatitis EAACI Guidelines on Allergen Immunotherapy: House dust mite-driven allergic asthma EAACI Guidelines on allergen immunotherapy: IgE-mediated food allergy EAACI guidelines on allergen immunotherapy: Hymenoptera venom allergy Medical algorithms: Management of chronic rhinosinusitis Hospitalization Rates and Characteristics of Patients Hospitalized with Laboratory-Confirmed Coronavirus Disease 2019 -COVID-NET, 14 States The characteristics of 50 hospitalized COVID-19 patients with and without ARDS Three-Year Safety and Efficacy of Benralizumab for Adolescent Patients with Severe, Uncontrolled Asthma: Results of the BORA Extension Study Position statement of expert panel of the Polish Allergology Society on the management of patients with bronchial asthma and allergic diseases during SARS-Cov-2 pandemics This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved