key: cord-0707397-4l2hqnve authors: Ding, Mei; Dong, Xiang; Sun, Yuan‐li; Sokolowska, Milena; Akdis, Mübeccel; van de Veen, Willem; Azkur, Ahmet Kursat; Azkur, Dilek; Akdis, Cezmi A.; Gao, Ya‐dong title: Recent advances and developments in COVID‐19 in the context of allergic diseases date: 2021-09-21 journal: Clin Transl Allergy DOI: 10.1002/clt2.12065 sha: e24f2a34234f9e56487f6a3d72bcd52c3d468b09 doc_id: 707397 cord_uid: 4l2hqnve BACKGROUND: Since the first reports of coronavirus disease 2019 (COVID‐19) in Wuhan, China, in December 2019, there have been 198 million confirmed cases worldwide as of August 2021. The scientific community has joined efforts to gain knowledge of the newly emerged virus named severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the immunopathological mechanisms leading to COVID‐19, and its significance for patients with allergies and asthma. METHODS: Based on the current literature, recent advances and developments in COVID‐19 in the context of allergic diseases were reviewed. RESULTS AND CONCLUSIONS: In this review, we discuss the prevalence of COVID‐19 in subjects with asthma, attacks of hereditary angioedema, and other allergic diseases during COVID‐19. Underlying mechanisms suggest a protective role of allergy in COVID‐19, involving eosinophilia, SARS‐CoV‐2 receptors expression, interferon responses, and other immunological events, but further studies are needed to fully understand those associations. There has been significant progress in disease evaluation and management of COVID‐19, and allergy care should continue during the COVID‐19 pandemic. The European Academy of Allergy & Clinical Immunology (EAACI) launched a series of statements and position papers providing recommendations on the organization of the allergy clinic, handling of allergen immunotherapy, asthma, drug hypersensitivity, allergic rhinitis, and other allergic diseases. Treatment of allergies using biologics during the COVID‐19 pandemic has also been discussed. Allergic reactions to the COVID‐19 vaccines, including severe anaphylaxis, have been reported. Vaccination is a prophylactic strategy that can lead to a significant reduction in the mortality and morbidity associated with SARS‐CoV‐2 infection, and in this review, we discuss the proposed culprit components causing rare adverse reactions and recommendations to mitigate the risk of anaphylactic events during the administration of the vaccines. As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily affects the respiratory tract, a preliminary hypothesis based on knowledge from common airway viruses proposed that asthma and other respiratory comorbidities might aggravate susceptibility to SARS-CoV-2 infection and lead to a more severe clinical outcome. 1 However, early data from Wuhan reported a lower prevalence of asthma among COVID-19 cases. 2 Similar findings were observed in Italy, Brazil, and Russia, [3] [4] [5] [6] even in severe asthma patients. 7, 8 Other studies also suggested that asthma was not associated with delayed viral clearance, 9 poor clinical outcome, 4,10-12 and mortality rate. 8 Moreover, allergic status in children did not increase COVID-19 incidence and its severity. 13, 14 In contrast, published data in the United States and United Kingdom (UK) indicated an increased prevalence of COVID-19 in patients with asthma. [15] [16] [17] Severe asthma treated with a high dose of inhaled corticosteroid (ICS) + long-acting beta 2-agonist (LABA) presented a higher Intensive Care Unit admission rate due to COVID-19. 18, 19 Moreover, epidemiologic data from Korean disease Control and Prevention showed asthma was associated with an increased risk of mortality and worse clinical outcomes of COVID-19. 20 Skevaki et al. also suggested a complex relationship between prevalence and severity of COVID-19 and allergy/asthma by reviewing more comprehensive epidemiologic data from different countries. 21, 22 There are multiple factors that can account for these inconsistent findings including atopic status, 23 asthma phenotype, 24, 25 eosinophil counts, 24 lockdown regulations, 12, 26 dietary habits, [27] [28] [29] [30] [31] airborne pollen concentrations, 32, 33 air pollution, 34 climate, 35 and comorbidities 12 (Figure 1 ). Respiratory atopy was suggested to have a protective role against severe lung disease in COVID-19 patients with viral pneumonia. 23 However, in contrast to patients with concomitant allergic rhinitis and asthma, allergic rhinitis alone was not regarded as a comorbidity that could modify susceptibility to SARS-CoV-2 infection as there was no significant difference in ACE2 gene expression between allergic rhinitis subjects and controls. 36 The asthma phenotype was found to be a strong determinant of disease severity. In a study from Stanford University, allergic asthma was found to mitigate the risk of hospitalization for COVID-19 compared to patients with non-allergic asthma (OR, 0.52). 24 In addition, patients with non-allergic asthma were more susceptible to SARS-CoV-2 infection and unfavorable clinical outcomes than patients with allergic asthma in a South Korean study. 25 Lower eosinophil counts were a predictive biomarker of severe disease progression independent of asthma phenotype. 24 Intriguingly, the prevalence of allergic diseases showed heterogeneous patterns during the COVID-19 pandemic. Childhood asthma presented better outcomes with fewer asthma exacerbations leading to a reduced number of emergency visits and hospitalizations. Moreover, 66% of pediatric asthma patients had improved asthma control as measured by the improved forced expiratory volume in one second (FEV1) and the peak expiratory flow (PEF). 37 In contrast, the number of hereditary angioedema attacks was notably increased due to restriction measures-related anxiety, depression, stress and fear of COVID-19. 38, 39 A survey based on 14 member countries commissioned by the Asia Pacific Association of Allergy Asthma and Clinical Immunology (APAAACI) indicated an increased prevalence of allergic diseases among healthcare workers during the COVID-19 pandemic, for example, ocular and airway allergy with extended use of surgical masks and eye protection; skin allergy due to prolonged use of gloves, protective equipment and frequent handwashing. 40 Systemic allergic reactions during the pandemic seemed to be drastically reduced as indicated by the number of patients attending an Emergency Department Unit in the UK, from 62 in the first half of pre-pandemic 2019 to 10 in the same period of 2020. The clinical F I G U R E 1 Potential factors associated with the prevalence and outcome of allergy in COVID-19 patients. Atopic status is suggested to be associated with lower risk of SARS-CoV-2 infection. Asthma phenotype is found to be a strong determinant of disease severity in COVID-19 with preexisting asthma. Lower eosinophil count is considered as predictive biomarker of severe COVID-19. Airborne pollen concentration, dietary habits, lockdown regulations, climate and comorbidities might be responsible for inconsistent findings of prevalence of allergy in COVID-19 patients manifestations presented before the pandemic by 52% of patients were classified as mild, according to the Brown grading system, whilst during the pandemic the majority of patients (80%) experienced moderate systemic allergic reactions. 41 Allergy or atopy is characterized by a type 2 (T2) immune response against external antigens in individuals, in which genetic predisposition plays a major role. 42 ACE2 gene expression was downregulated in the airway epithelial cells, including in the nasal polys, and the olfactory neuroepithelium. Chronic rhinosinusitis with nasal polyps (CRSwNP) was characterized by a type 2 immune signature with increased eosinophil counts in the olfactory mucosa. Moreover, ACE2 expression was negatively correlated with the number of eosinophils. 47 Pre-existing eosinophilia was found to have a protective role as observed by a reduction in hospitalization with SARS-CoV-2 infection. 48 In contrast, eosinopenia was predictive of poor disease outcome 49 and was usually found in deceased COVID-19 patients. 50-52 A higher eosinophil count is a biomarker of allergic inflammation, and allergic subjects with eosinophilia were less susceptible to SARS-CoV-2 infection. 50 Eosinophils were demonstrated to promote antiviral immunity in animal models. 53 They are known to induce secretion of Th1 cytokines, generation of superoxide and nitric oxide (NO), and recruitment of CD8 + T cells against respiratory virus infection. Eosinophil-derived enzymes have been proposed to neutralize the virus via a ribonuclease-dependent mechanism. 54 A lower eosinophil count was associated with CD8 + T cell depletion, which might be related to a Th17 inflammatory pattern in severe COVID-19 patients. [55] [56] [57] Further studies are warranted to confirm these findings. Although type I and III interferons (IFN-α/β and -λ respectively) are essential to abrogate viral infection, 3,58,59 excessive or prolonged type I IFN production promotes the release of proinflammatory chemokines that contribute to poor disease outcome by disrupting lung epithelial regeneration. 60 Although the COVID-19 pandemic significantly impaired health care, management of allergic diseases was still ongoing by adhering to preventive measures. For example, there has been a shift of chronic DING ET AL. -3 of 10 urticaria consultation from face-to-face (decreased by 62%) towards telemedicine (increased by over 600%). 74 Telecommunication tools have been implemented during the COVID-19 pandemic, [75] [76] [77] facilitating communication between doctors and patients whilst maintain social distancing. During the pandemic, mild-to-moderate or wellcontrolled asthma patients were recommended to seek consultation online. 78 Outpatient service was more appropriate for patients whose symptoms were not resolved or worsened with the escalation of medication. 78 Coughing at total lung capacity generated the highest mass of exhaled particles. This data indicated that in the absence of coughing, spirometry did not pose a significant risk for viral transmission, which might be potentially beneficial for asthma diagnosis and follow-up management. 82 Telemedicine ensures the safety of both patients and healthcare professionals during the COVID-19 pandemic, for example, quantitative measuring of olfactory dysfunction using psychophysical analyses were remotely performed. [83] [84] [85] However, sputum induction, which is a widely used technique to evaluate airway inflammation and specially to classify the inflammatory phenotype of asthma can only be conducted in a hospital setting. As sputum induction generates aerosols it presents a high risk of viral transmission. In this case, the medical protocols were adapted to guarantee the safety of the patients and healthcare professionals, such as the use of personal protection equipment, and alternative sampling and processing procedures. 86 EAACI launched a series of statements and position papers providing official recommendations for the treatment of drug hypersensitivity, allergic rhinitis, asthma, and other allergic diseases during the COVID-19 pandemic (Table 1) , contributing to virus-specific antibodies production. In atopic subjects, IgE released by PC might play a negative role in the IFN-α/β pathway regulation practical considerations on the organization of allergic clinics. 93 In summary, atopic diseases should be treated following current guidelines even among patients at risk or with active SARS-CoV-2 infection. These guidelines should be continuously updated as we gain knowledge of this evolving coronavirus. An APAAACI survey reported a decrease in AIT (46.1%) and immunosuppressive therapies (23.1%) in allergic patients during the COVID-19 pandemic. 40 Unfortunately, patients with non-adherent subcutaneous immunotherapy (SCIT) for house dust mite allergy (≥2-month delay) had higher median medication scores, visual analogue scale for quality of life, and total symptom scores. 94 On the other hand, venom-specific immunotherapy was safely administered in Spanish clinics following a strict sanitary protocol. 95 Additionally, there was no reduced tolerability even among patients combined with early COVID-19 symptoms and/or with positive SARS-CoV-2 results. 96 Therefore, patients should be encouraged to adhere to treatment during the pandemic to ensure a successful outcome of immunotherapy. 94, 97, 98 Biological therapeutics targeting type 2 inflammation pathways have been adopted in a wide range of allergic diseases. [99] [100] [101] The safety of biologicals during the pandemic has come into question as these are known to interact with T2 cytokines and may interfere with eosinophil-mediated antiviral activity. Reduced production of IgG and IgM and absence of IgA antibodies were observed in a severe asthmatic patient undergoing dupilumab treatment. 102 Overall, a decreased (30.8%) use of biologicals in severe asthma was reported in an APAAACI survey. 40 Drug hypersensitivity reactions (DHRs) DHRs occurred rarely and most were nonimmediate cutaneous reactions. Disease-related exanthems were the most characteristic differential diagnosis of DHRs. [90] Asthma Inhaled corticosteroids or prescribed long-term oral corticosteroids should continue. Spacers of large capacity are suggested to replace nebulization in patients with active SARS-CoV-2 infection. [91] Allergic rhinitis Use of intranasal corticosteroids (including spray) should be continued. [92] DING ET AL. vaccination. 136 An allergological work-up for patients with a possible risk of severe hypersensitivity reactions is recommended. 137 The patients should be evaluated with skin tests for the vaccine and its excipients. Alternative vaccines that do not contain the suspected components could be considered in case of a positive skin result. In all cases, the vaccination should be followed with a minimum 15-min observation. The vaccine should be administered in escalated doses for patients at a high risk of severe hypersensitivity reactions. An adrenaline (epinephrine) injector should be readily available to treat any anaphylactic event. 120, 133, 136, 138 In conclusion, current evidence shows that allergy might play a There is a current need to improve our understanding of the underlying mechanisms involved in the vaccines adverse reactions and their culprit components to ensure their safety and public compliance. None. None of the authors has any conflicts of interest to declare. Asthma and COVID-19: is asthma a risk factor for severe outcomes? Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan Is asthma protective against COVID-19? Asthmatic patients and COVID-19: different disease course? Low prevalence of bronchial asthma and chronic obstructive lung disease among intensive care unit patients with COVID-19 Asthma phenotypes, comorbidities, and disease activity in COVID-19: the need of risk stratification Severe asthma in adults does not significantly affect the outcome of COVID-19 disease: 6 of 10 -DING ET AL. results from the Italian Severe Asthma Registry COVID-19 in Severe Asthma Network in Italy (SANI) patients: clinical features, impact of comorbidities and treatments Characterization of asthma and risk factors for delayed SARS-CoV-2 clearance in adult COVID-19 inpatients in Daegu Asthma among hospitalized patients with COVID-19 and related outcomes Clinical course and outcomes of patients with asthma hospitalized for severe acute respiratory syndrome coronavirus 2 pneumonia: a single-center, retrospective study Reply to: Kow CS et al. Are severe asthma patients at higher risk of developing severe outcomes from COVID-19? Eleven faces of coronavirus disease 2019 COVID-19: a series of important recent clinical and laboratory reports in immunology and pathogenesis of SARS-CoV-2 infection and care of allergy patients Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019 -COVID-NET, 14 states Associations with Covid-19 hospitalisation amongst 406,793 adults: the UK Biobank prospective cohort study Update on asthma prevalence in severe COVID-19 patients Prevalence and characterization of asthma in hospitalized and nonhospitalized patients with COVID-19 Are severe asthma patients at higher risk of developing severe outcomes from COVID-19? Association between asthma and clinical mortality/morbidity in COVID-19 patients using clinical epidemiologic data from Korean Disease Control and Prevention Asthma-associated risk for COVID-19 development SARS-CoV-2 infection and COVID-19 in asthmatics: a complex relationship Atopic status protects from severe complications of COVID-19 Asthma phenotypes, associated comorbidities, and long-term symptoms in COVID-19 Allergic disorders and susceptibility to and severity of COVID-19: a nationwide cohort study The effect of human mobility and control measures on the COVID-19 epidemic in China Reply to "cabbage and COVID-19 Cabbage and COVID-19 Cabbage and fermented vegetables: from death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19 Is diet partly responsible for differences in COVID-19 death rates between and within countries? Nrf2-interacting nutrients and COVID-19: time for research to develop adaptation strategies Higher airborne pollen concentrations correlated with increased SARS-CoV-2 infection rates, as evidenced from 31 countries across the globe Adding the variable of environmental complexity into the COVID-19 pandemic equation Pros and cons for the role of air pollution on COVID-19 development Climate and COVID-19: converging crises Angiotensin-converting enzyme II expression and its implication in the association between COVID-19 and allergic rhinitis Childhood asthma outcomes during the COVID-19 pandemic: findings from the PeARL multi-national cohort Psychological distress and COVID-19-related stressors reported in a longitudinal cohort of US adults in April and Impact of anxiety, stress and depression related to COVID-19 pandemic on the course of hereditary angioedema with C1-inhibitor deficiency Asia-Pacific perspectives on the COVID-19 pandemic Anaphylaxis in the emergency department unit: before and during COVID-19 Type 2 cytokines: mechanisms and therapeutic strategies Genetic predisposition to allergic diseases is inversely associated with risk of COVID-19 Association of respiratory allergy, asthma, and expression of the SARS-CoV-2 receptor ACE2 Type 2 inflammation modulates ACE2 and TMPRSS2 in airway epithelial cells Type 2 and interferon inflammation regulate SARS-CoV-2 entry factor expression in the airway epithelium ACE2 downregulation in olfactory mucosa: eosinophilic rhinosinusitis as COVID-19 protective factor? Eosinophilia in asthma patients is protective against severe COVID-19 illness Eosinopenia and elevated C-reactive protein facilitate triage of COVID-19 patients in fever clinic: a retrospective case-control study Clinical features of 85 fatal cases of COVID-19 from Wuhan. A retrospective observational study The role of circulating eosinophils on COVID-19 mortality varies by race/ ethnicity Eosinopenia is associated with greater severity in patients with coronavirus disease 2019 Eosinophils promote antiviral immunity in mice infected with influenza A virus Eosinophil responses during COVID-19 infections and coronavirus vaccination TH17 responses in cytokine storm of COVID-19: an emerging target of JAK2 inhibitor Fedratinib Eosinophils regulate dendritic cells and Th2 pulmonary immune responses following allergen provocation COVID-19, chronic inflammatory respiratory diseases and eosinophils-Observations from reported clinical case series Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients Global absence and targeting of protective immune states in severe COVID-19 Baricitinib for COVID-19: a suitable treatment?-Authors' reply Type I and III interferons disrupt lung epithelial repair during recovery from viral infection Type I, II, and III interferon signatures correspond to COVID-19 disease severity Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice Interferon at the crossroads of allergy and viral infections Aberrant function of peripheral blood myeloid and plasmacytoid dendritic cells in atopic dermatitis patients Reciprocal regulatory effects of IFN-gamma and IL-4 on the in vitro development of human Th1 and Th2 clones Th2 cytokines impair innate immune responses to rhinovirus in respiratory epithelial cells Immunology of COVID-19: mechanisms, clinical outcome, diagnostics, and perspectives-A report of the European Academy of allergy and clinical immunology (EAACI) Clinical characteristics of COVID-19 patients combined with allergy SARS-CoV-2, COVID-19, skin and immunology -what do we know so far? Dermatology and COVID-19 Distribution of ACE2, CD147, CD26, and other SARS-CoV-2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID-19 risk factors SARS-CoV-2 receptor ACE2 protein expression in serum is significantly associated with age The global impact of the COVID-19 pandemic on the management and course of chronic urticaria Covid-19 and health care's digital revolution Virtually perfect? Telemedicine for Covid-19 Virtual health care in the era of COVID-19 Asthma control, self-management, and healthcare access during the COVID-19 epidemic in Beijing COVID-19: pandemic contingency planning for the allergy and immunology clinic Real-life impact of COVID-19 pandemic lockdown on the management of pediatric and adult asthma: a survey by the EAACI Asthma Section Airborne or droplet precautions for health workers treating COVID-19? Small droplet emission in exhaled breath during different breathing manoeuvres: implications for clinical lung function testing during COVID-19 Telemedicine allows quantitative measuring of olfactory dysfunction in COVID-19 Olfactory dysfunction in COVID-19: diagnosis and management Widespread smell testing for COVID-19 has limited application Multidisciplinary consensus on sputum induction biosafety during the COVID-19 pandemic Management of patients with chronic rhinosinusitis during the COVID-19 pandemic-An EAACI position paper Management of ocular allergy Managing ocular allergy in the time of COVID-19 Diagnosis and management of the drug hypersensitivity reactions in Coronavirus disease 19: an EAACI Position Paper ARIA-EAACI statement on asthma and COVID-19 Intranasal corticosteroids in allergic rhinitis in COVID-19 infected patients: an ARIA-EAACI statement COVID-19 pandemic: practical considerations on the organization of an allergy clinic-An EAACI/ ARIA Position Paper Adherence to subcutaneous immunotherapy with aeroallergens in real-life practice during the COVID-19 pandemic Treating venom allergy during COVID-19 pandemic: management of venom allergen immunotherapy during the COVID-19 outbreak in Spain COVID-19 pandemic and allergen immunotherapy -an EAACI survey Treating venom allergy during COVID-19 pandemic Handling of allergen immunotherapy in the COVID-19 pandemic: an ARIA-EAACI statement The anti-inflammatory effects of omalizumab confirm the central role of IgE in allergic inflammation Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis Efficacy and safety of dupilumab in perennial allergic rhinitis and comorbid asthma Dupilumab, severe asthma airway responses, and SARS-CoV-2 serology Management of patients with atopic dermatitis undergoing systemic therapy during COVID-19 pandemic in Italy: data from the DA-COVID-19 registry Could an unrelated live attenuated vaccine serve as a preventive measure to dampen septic inflammation associated with COVID-19 infection? mBio COVID-19 in a patient with severe asthma treated with Omalizumab COVID-19 in severe asthmatic patients during ongoing treatment with biologicals targeting type 2 inflammation: results from a multicenter Italian survey A compendium answering 150 questions on COVID-19 and SARS-CoV-2 Considerations on biologicals for patients with allergic disease in times of the COVID-19 pandemic: an EAACI statement BNT162b2 mRNA covid-19 vaccine effectiveness among health care workers Preliminary findings of mRNA covid-19 vaccine safety in pregnant persons Safety and efficacy of singledose Ad26.COV2.S vaccine against covid-19 Safety and efficacy of NVX-CoV2373 covid-19 vaccine Effectiveness of COVID-19 vaccines against the B.1.617.2 (delta) variant Prevention and attenuation of COVID-19 with the BNT162b2 and mRNA-1273 vaccines Oxford-AstraZeneca COVID-19 vaccine efficacy Safety, immunogenicity, and efficacy of the BNT162b2 COVID-19 vaccine in adolescents Safety and immunogenicity of two RNA-based COVID-19 vaccine candidates Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine Allergic reactions including anaphylaxis After receipt of the first dose of pfizer-BioNTech COVID-19 vaccine ARIA-EAACI statement on severe allergic reactions to COVID-19 vaccines -an EAACI-ARIA Position Paper Vaccines and allergic reactions: the past, the current COVID-19 pandemic, and future perspectives Planning for a COVID-19 vaccination program Early rate reductions of SARS-CoV-2 infection and COVID-19 in BNT162b2 vaccine recipients Allergic reactions to the first COVID-19 vaccine: a potential role of polyethylene glycol? Allergic reactions to COVID-19 vaccinationsunveiling the secret(s) COVID-19 vaccine anaphylaxis: PEG or not? COVID-19 vaccine anaphylaxis: IgE, complement or what else? A reply to: COVID-19 vaccine anaphylaxis: PEG or not? Allergenic components of the mRNA-1273 vaccine for COVID-19: possible involvement of polyethylene glycol and IgG-mediated complement activation Vaccination management in children and adults with mastocytosis Cutaneous and systemic mastocytosis in children: a risk factor for anaphylaxis? COVID-19 vaccines and the role of other potential allergenic components different from PEG. A reply to Hypersensitivity reaction to human papillomavirus vaccine due to polysorbate 80 Other excipients than PEG might cause serious hypersensitivity reactions in COVID-19 vaccines Systemic allergic reactions following immunization with human diploid cell rabies vaccine A review of licensed viral vaccines, some of their safety concerns, and the advances in the development of investigational viral vaccines EAACI statement on the diagnosis, management and prevention of severe allergic reactions to COVID-19 vaccines Patients with suspected allergic reactions to COVID-19 vaccines can be safely revaccinated after diagnostic workup Management of anaphylaxis due to COVID-19 vaccines in the elderly Recent advances and developments in COVID-19 in the context of allergic diseases