Considerations on biologicals for patients with allergic disease in times of the COVID19 pandemic: An EAACI statement



# Abstract
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 number of 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 pro-inflammatory 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.
Studies focusing on severe allergic phenotypes are lacking. At present, noninfected 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, are demanded.

## | introduc ti on
The outbreak leading to the pandemic of SARS-CoV-2-induced coronavirus disease 2019 (COVID-19) has pushed healthcare systems to 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.

## | immunolog ic al fe ature s of sar s -cov-infec ti on in the conte x t of t ype infl ammation
Both innate and adaptive immune responses participate in antiviral 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 Antibodysecreting cells and T follicular helper cells are instrumental in the production of specific antiviral IgA, IgM, and IgG antibodies early on. [bib_ref] Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in..., Channappanavar [/bib_ref] [bib_ref] Breadth of concomitant immune responses prior to patient recovery: a case report..., Thevarajan [/bib_ref] [bib_ref] Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19), Guo [/bib_ref] 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. [bib_ref] Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology, Channappanavar [/bib_ref] [bib_ref] Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology, Channappanavar [/bib_ref] [bib_ref] Immunological responses against SARS-coronavirus infection in humans, Xu [/bib_ref] and, more recently, COVID-19 patients 9 suggest an overshooting immune response in severe cases with widespread lung damage and disease aggravation around 7-14 days after onset.
Those severe COVID-19 patients may also experience a 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 by an exaggerated release of pro-inflammatory cytokines, such as IL-1, IL-6, IL-8, and TNF- . Consequently, these highly increased pro-inflammatory cytokines are believed to be potential targets for biological therapy. These type 1-and type 3-driven inflammatory responses are counteracted by anti-inflammatory 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. [bib_ref] Eosinophils capture viruses, a capacity that is defective in asthma, Sabogal Pineros [/bib_ref] 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 .

## | sar s -cov-2 infec ti on and allerg i c d is e a s e
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, 2020, only 6 studies presented disease characteristics of SARS-CoV-2 infection on patients with allergy or atopic diseases as a comorbidity ; Supplementary Material). While in a study including F I G U R E 1 Cellular networks during SARS-CoV-2 infection. Initially, infection with the SARS-CoV-2 induces both humoral and cellular (innate and adaptive) immune responses. Recruitment of antibody-secreting cells (ASC) and interaction with T follicular helper cells (Tfh) occurs early before the resolution of symptoms and leads to the production of IgA, IgM, and IgG against viral nucleoprotein (NP) and surface spike protein receptor-binding domain (RBD). SARS-CoV-2 binding antibodies may participate in tissue damage by macrophage activation via FcRI. SARS-CoV-2 infects several types of cells (alveolar lung cells, macrophages, endothelial cells, lymphocytes) stimulating type I IFN production, which is crucial for the protection of uninfected cells and the enhancement of natural killer (NK) cell cytotoxic activity. Virus-cell interactions lead to the release of mediators. The secretion of large amounts of cytokines and chemokines is promoted in infected cells and effector cell populations in response to virus. These mediators, in turn, alert tissue-resident lymphocytes (including also innate lymphoid cells, ILCs) and recruit other leukocytes, predominantly in the lungs.Dendritic cells function as sensor cells and present virus antigens to T cells. This process leads to T-cell activation and differentiation, including the production of cytokines associated with Th1 and Th17 profile, and subsequently activates CD8 + cytotoxic T cells. Both, inflammation and cell damage, induce and result in the release of danger signals and alarmins (IL-33, IL-25, TSLP) that may promote both Th2 cells and ILC2 cells. The immune network during the course of infection includes the involvement of regulatory T (Treg) cells, able to secrete IL-10 and TGF- 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. [bib_ref] Covid-19 in Critically Ill Patients in the Seattle Region -Case Series, Bhatraju [/bib_ref] [bib_ref] Eleven Faces of Coronavirus Disease, Dong [/bib_ref] [bib_ref] Clinical Features of 69 Cases With Coronavirus Disease, Wang [/bib_ref] [bib_ref] Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, Zhang [/bib_ref] None of these patients were on biologicals to treat their pre-existing allergic disease. In a recent report from the COVID-19-Associated

## | b i olog i c al ther apie s targ e ting t ype 2 infl ammation: ke y issue s
In the past years, new biological therapies for severe asthma, atopic dermatitis (AD), chronic rhinosinusitis with nasal polyps (CRSwNP), F I G U R E 2 Hypothesis of a favorable evolution of SARS-CoV-2 infection in the context of type 2 cytokine and regulatory cytokine responses. The hypothetical evolution of the antiviral immune response during SARS-CoV-2 infection may unfold as following: Lung injury triggered by virus is propagated by innate and adaptive immune system. Adaptive responses are triggered shortly after activation of the innate system. During the infection course, a dynamic balance between pro-inflammatory type 1 and Th17 cells as well as Treg populations and anti-inflammatory type 2 responses is upregulated. Both high levels of certain type 2 (IL-4, IL-13) and regulatory cytokines (IL-10, TGF-) could protect from worsening of lung tissue damage targeting different aspects of the type 2 immune response. [bib_ref] Precision medicine and phenotypes, endotypes, genotypes, regiotypes, and theratypes of allergic diseases, Agache [/bib_ref] [bib_ref] EAACI IG Biologicals task force paper on the use of biologic agents..., Boyman [/bib_ref] [bib_ref] Future research trends in understanding the mechanisms underlying allergic diseases for improved..., Breiteneder [/bib_ref] [bib_ref] Biologicals in allergic diseases and asthma: Toward personalized medicine and precision health:..., Palomares [/bib_ref] [bib_ref] Biologicals in atopic disease in pregnancy: an EAACI position paper, Pfaller [/bib_ref] [bib_ref] New biological treatments for asthma and skin allergies, Eyerich [/bib_ref] [bib_ref] The EAACI/GA(2)LEN/EDF/ WAO guideline for the definition, classification, diagnosis and management of..., Zuberbier [/bib_ref] [bib_ref] EUFOREA consensus on biologics for CRSwNP with or without asthma, Fokkens [/bib_ref] [bib_ref] Dupilumab reduces local type 2 pro-inflammatory biomarkers in chronic rhinosinusitis with nasal..., Jonstam [/bib_ref] 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  subunit of IL-5 receptor (IL-5R), 25 was also recently approved for uncontrolled eosinophilic severe asthma.
Dupilumab, a monoclonal antibody directed against the  subunit of the IL-4 receptor (IL-4R) 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.

## | b lo cking t ype 2 infl ammati on and vir al infec tions
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. [bib_ref] Targeting Antiviral Pathways for Treatment of Allergic Diseases, Rowe [/bib_ref] There is no evidence, which suggests immune response to COVID-19 will be impaired in asthma patients treated with anti-IL5, anti-IL5Ra, anti-IL4/IL13, or anti-IgE medications. In the absence of any data indicating a potential for harm, it would be reasonable to continue administration of biologic agents during the COVID-19 pandemic in patients for whom such agents are clearly indicated and have been effective.
ACAAI www.colle ge.acaai.org April 8, 2020
For patients with severe asthma currently on a biologic therapy, there is no information at this time that these treatments should be stopped. These severe asthma patients are at an increased risk to COVID-19 infection, and optimal control of their chronic condition is of upmost importance. - Unavailable therapy with biologics may lead to many patients requiring treatment with systemic steroids and potentially negative impact on immune responses directed against SARS-CoV-2 - Stopping treatment with biologics may lead to worsening of the underlying disease, which may therefore provide negative influence on the course of acquired COVID-19 disease. According to WHO, patients with chronic lung disease (eg, such as asthma) may be prone to more severe disease. a. viral asthma exacerbations occur less frequently and with lower severity under treatment with biologics b. those immune processes targeted by biologics most probably do not affect virus defense - Based on current knowledge, we therefore recommend to maintain treatment based on a joint agreement between treating physician and patient.

## Aad
WAO worldallergy.org April 8, 2020
For patients: "There is currently no evidence that inhaled corticosteroids (nasal or bronchial), antihistamines or biologic medications have any effect on the risk of contracting COVID-19. If you stop or modify your treatment, you run the risk that your allergic disease, particularly your asthma control, could become worse, causing you to need rescue medical treatment or be admitted to the hospital." https://www.world aller gy.org/UserF iles/file/Aller gic_patie nts_during_COVID -19.pdf PAS [bib_ref] Position statement of expert panel of the Polish Allergology Society on the..., Kowalski [/bib_ref] - It is recommended to continue biologic therapy with anti-IgE or anti-IL-5 in patients with severe asthma.
- It is acceptable to start and then continue biologic therapy with anti-IgE or anti-IL-5 antibodies in patients with severe bronchial asthma in accordance with the current Biological Treatment Programme of the National Health Fund. - Continuation and, in specific cases, initiation of biologic therapy with anti-IgE antibodies (omalizumab) in patients with severe chronic urticaria are acceptable.
(AE) in severe eosinophilic asthma. [bib_ref] Efficacy and safety of treatment with biologicals (benralizumab, dupilumab, mepolizumab, omalizumab and..., Agache [/bib_ref] For anti-IgE (omalizumab) and
anti-IL-4R (dupilumab) treatments, rate ratios were rather small. [bib_ref] Efficacy and safety of treatment with biologicals (benralizumab, dupilumab, mepolizumab, omalizumab and..., Agache [/bib_ref] Benralizumab and omalizumab showed an increase in AEs with lowto-moderate certainty in severe allergic asthma. [bib_ref] Efficacy and safety of treatment with biologicals (benralizumab, dupilumab and omalizumab) for..., Agache [/bib_ref] There was an increased rate of dupilumab-related AEs (low certainty) in severe asthma. [bib_ref] Efficacy and safety of treatment with dupilumab for severe asthma: A systematic..., Agache [/bib_ref] Data from clinical trials demonstrated good safety profiles of biologicals with regard to viral infections of the upper respiratory tract . 36-38

## | pr ac ti c al and clini c al recommendations

## | recommendations from national societies
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 (

## | eaaci statement on the management of allergic disease with type 2 targeting biologicals during covid-19 pandemic
The key recommendation for an accurate management of nonin- cations as recommended by current guidelines) should be continued, as described for asthma, AD, CRSwNP, and CSU. [bib_ref] The EAACI/GA(2)LEN/EDF/ WAO guideline for the definition, classification, diagnosis and management of..., Zuberbier [/bib_ref] [bib_ref] EUFOREA consensus on biologics for CRSwNP with or without asthma, Fokkens [/bib_ref] [bib_ref] EAACI Guidelines on Allergen Immunotherapy: House dust mite-driven allergic asthma, Agache [/bib_ref] [bib_ref] EAACI Guidelines on allergen immunotherapy: IgE-mediated food allergy, Pajno [/bib_ref] [bib_ref] EAACI guidelines on allergen immunotherapy: Hymenoptera venom allergy, Sturm [/bib_ref] [bib_ref] Medical algorithms: Management of chronic rhinosinusitis, Fokkens [/bib_ref] Surgical interventions for CRSwNP should be delayed in any case possible. .
Once resolution/recovery of the disease is established (eg, via a negative SARS-CoV-2 test) but no shorter than 2 weeks postonset of the disease/positive testing, the re-administration of the biological should be re-initiated .

## | con clus ions
In conclusion, current evidence does not suggest a higher risk for severe COVID-19 in allergic individuals but data that allow esti- of such data is imperative for future data-informed adaptations of these guidelines.

## Co n fli c t o f i nte r e s t
[fig] Hospitalization: Surveillance Network based on data from 14 US states from March 1, 2020, to March 30, 2020, 17% of hospitalized COVID-19 patients had asthma as a comorbidity. The highest percentage was in the 18-to 49-year-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 COVID-19. [/fig]