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Asthma-associated risk for COVID-19 development

  • Chrysanthi Skevaki
    Affiliations
    Institute of Laboratory Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Philipps Universität Marburg, German Center for Lung Research (DZL), Marburg, Germany

    German Center for Lung Research (DZL), Marburg, Germany
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  • Antonina Karsonova
    Affiliations
    Department of Clinical Immunology and Allergology, Laboratory of Immunopathology, Sechenov University, Moscow, Russia
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  • Alexander Karaulov
    Affiliations
    Department of Clinical Immunology and Allergology, Laboratory of Immunopathology, Sechenov University, Moscow, Russia
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  • Min Xie
    Affiliations
    Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Harald Renz
    Correspondence
    Corresponding author: Harald Renz, MD, Institute of Laboratory Medicine, Philipps-University Marburg, Baldinger Straße, 35043 Marburg, Germany.
    Affiliations
    Institute of Laboratory Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Philipps Universität Marburg, German Center for Lung Research (DZL), Marburg, Germany

    German Center for Lung Research (DZL), Marburg, Germany

    Department of Clinical Immunology and Allergology, Laboratory of Immunopathology, Sechenov University, Moscow, Russia
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Published:September 28, 2020DOI:https://doi.org/10.1016/j.jaci.2020.09.017
      The newly described severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for a pandemic (coronavirus disease 2019 [COVID-19]). It is now well established that certain comorbidities define high-risk patients. They include hypertension, diabetes, and coronary artery disease. In contrast, the context with bronchial asthma is controversial and shows marked regional differences. Because asthma is the most prevalent chronic inflammatory lung disease worldwide and SARS-CoV-2 primarily affects the upper and lower airways leading to marked inflammation, the question arises about the possible clinical and pathophysiological association between asthma and SARS-CoV-2/COVID-19. Here, we analyze the global epidemiology of asthma among patients with COVID-19 and propose the concept that patients suffering from different asthma endotypes (type 2 asthma vs non–type 2 asthma) present with a different risk profile in terms of SARS-CoV-2 infection, development of COVID-19, and progression to severe COVID-19 outcomes. This concept may have important implications for future COVID-19 diagnostics and immune-based therapy developments.

      Key words

      Abbreviations used:

      ACE-2 (Angiotensin-converting enzyme-2), COVID-19 (Coronavirus disease 2019), HI (Heterologous immunity), ICS (Inhaled corticosteroid), TMPRSS2 (Transmembrane proteases serine 2)

      Global epidemiology

       The susceptibility of patients with asthma to COVID-19

      First epidemiologic studies of the coronavirus disease 2019 (COVID-19) pandemic in China included 72,314 case records, of which 44,672 were classified as confirmed cases of COVID-19 (diagnosis based on positive viral nucleic acid test result on throat swab samples) and did not identify asthma as a risk factor of severe COVID-19.

      Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention [published online ahead of print 2020]. JAMA. https://doi.org/10.1001/jama.2020.2648.

      A total of 548 patients with COVID-19 admitted to Tongji Hospital were retrospectively analyzed and 5 of 548 patients had asthma (0.9%).
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      Zhongnan Hospital of Wuhan University retrospectively analyzed 140 hospitalized patients with COVID-19 and also concluded that allergic disease or asthma is not a risk factor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
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      The prevalence of asthma in the adult population of Wuhan is 6.4%. The prevalence of asthma among patients with COVID-19 was subsequently reported in several other countries and regions. Studies from Russia, Saudi Arabia, and Brazil confirmed the lower rates of asthma among patients with COVID-19 (1.8%, 2.7%, and 1.5% respectively).

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      The prevalence of asthma among patients with COVID-19 in Mexico (3.6%),

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      which like Brazil is also in Latin America, was relatively high compared with that in Brazil. Asthma was not mentioned among the comorbidity list of COVID-19 in a retrospective Indian epidemiological study.
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      In Europe, the prevalence of asthma varied from country to country, with Swedish and Italian cohort studies reporting relatively low rates of asthma, 1.8% and 2.6% (Sweden) and 1.96% and 1.92% (Italy)
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      (see Table E1 in this article’s Online Repository at www.jacionline.org). Another retrospective case series of 1591 patients hospitalized with laboratory-confirmed COVID-19 in the Lombardy region of Italy did not mention patients with asthma.
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      A cohort of patients with COVID-19 in a major teaching hospital in Europe.

      Prieto-Albhambra D, Ballo E, Coma-Redon E, Mora N, Aragon M, Prats-Uribe A, et al. Hospitalization and 30-day fatality in 121,263 COVID-19 outpatient cases [published online ahead of print 2020]. medRxiv. https://doi.org/10.1101/2020.05.04.20090050.

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      The prevalence of asthma in the general population in Italy, Spain, and Ireland is 6.0%, 5.0%, and 7.0%, respectively
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      Asthmatic patients in COVID-19 outbreak: few cases despite many cases.
      ,
      ClinicalTrials.gov Identifier: NCT03137043
      Prevalence of severe asthma in Spanish hospitals—full text view.
      , (Fig 1, A and B).
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      Oliveira TB, Persigo ALK, Ferrazza CC, Ferreira ENN, Veiga ABG. Prevalence of asthma, allergic rhinitis and pollinosis in a city of Brazil: a monitoring study [published online ahead of print 2020]. Allergol Immunopathol. https://doi.org/10.1016/j.aller.2020.03.010.

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      Figure thumbnail gr1
      Fig 1Asthma prevalence. A, Countries with high prevalence of asthma among COVID-19 comorbidities in comparison with asthma prevalence in the general population (high asthma-COVID-19 zone) are marked in red color. Countries with low/equal prevalence of asthma among COVID-19 comorbidities in comparison with asthma prevalence in the general population (low asthma-COVID-19 zone) are marked in green. B, Asthma prevalence (%) among patients with COVID-19 in comparison with the general population in various countries.
      • Caminati M.
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      • Bigni B.
      • Furci F.
      • et al.
      Asthmatic patients in COVID-19 outbreak: few cases despite many cases.
      ,
      ClinicalTrials.gov Identifier: NCT03137043
      Prevalence of severe asthma in Spanish hospitals—full text view.
      ,
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      • Zheng M.
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      • Zhang Y.
      • Bo M.Y.
      • et al.
      An increased prevalence of self-reported allergic rhinitis in major Chinese cities from 2005 to 2011.
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      Prevalence, risk factors, and management of asthma in China: a national cross-sectional study.
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      • Zhou X.
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      Prevalence and risk factors of asthma in mainland China. The CARE study.
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      • Khaltaev N.
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      • Antonini P.
      • et al.
      Chronic respiratory diseases and risk factors in 12 regions of the Russian Federation.
      • Agrawal S.
      • Pearce N.
      • Millett C.
      • Subramanian S.V.
      • Ebrahim S.
      Occupations with an increased prevalence of self-reported asthma in Indian adults.
      • Del-Rio-Navarro B.E.
      • Navarrete-Rodríguez E.M.
      • Berber A.
      • Reyes-Noriega N.
      • García-Marcos Álvarez L.
      The burden of asthma in an inner-city area: a historical review 10 years after Isaac.

      Oliveira TB, Persigo ALK, Ferrazza CC, Ferreira ENN, Veiga ABG. Prevalence of asthma, allergic rhinitis and pollinosis in a city of Brazil: a monitoring study [published online ahead of print 2020]. Allergol Immunopathol. https://doi.org/10.1016/j.aller.2020.03.010.

      • Musharrafieh U.
      • Tamim H.
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      A nationwide study of asthma correlates among adolescents in Saudi Arabia.
      However, recent studies from the United States and the United Kingdom indicated high rates of asthma in patients with COVID-19. The prevalence of asthma among patients with COVID-19 was 14.4% versus the national asthma prevalence of 8% to 9% in the United States. Asthma and inhaled corticosteroids (ICSs) were not associated with risk of hospitalization due to COVID-19.
      Centers for Disease Control and Prevention
      Asthma prevalence.
      A huge retrospective study included 11 acute care hospitals of a public hospital system and described demographic and clinical characteristics and outcomes of patients tested for COVID-19. Of the 22,254 patients who were tested, 13,442 patients tested positive, 6,248 required hospitalization, and 1,724 died. Asthma prevalence rate was 7% among positive patients and 11% among negative patients.

      Kalyanaraman Marcello R, Dolle J, Grami S, Adule R, Li Z, Tatem K, et al. Characteristics and outcomes of COVID-19 patients in New York City’s public hospital system [published online ahead of print 2020]. medRxiv. https://doi.org/10.1101/2020.05.29.20086645.

      A case series of 5700 patients with confirmed COVID-19 in the New York City area provides characteristics of hospitalized patients; asthma prevalence was determined as 9%.
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      The International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) study based on 16,749 patients with COVID-19 in the United Kingdom reported about 14% asthma prevalence.

      Docherty AB, Harrison EM, Green CA, Hardwick HE, Pius R, Norman L, et al. Features of 16,749 hospitalised UK patients with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol [published online ahead of print 2020]. medRxiv. https://doi.org/10.1101/2020.04.23.20076042.

      A population-based prospective cohort study analyzed data from the UK Biobank and reported about 17.9% prevalence of asthma in patients with COVID-19.

      Khawaja AP, Warwick AN, Hysi PG, Kastner A, Dick A, Khaw PT, et al. Associations with covid-19 hospitalisation amongst 406,793 adults. The UK Biobank prospective cohort study [published online ahead of print 2020]. medRxiv. https://doi.org/10.1101/2020.05.06.20092957. Available at: https://www.medrxiv.org/content/10.1101/2020.05.06.20092957v1.

      Another study that analyzed UK Biobank data reported an asthma rate of about 13% and added that adults with asthma had a higher risk of severe COVID-19.

      Zhu Z, Hasegawa K, Ma B, Fujiogi M, Camargo CA, Liang L. Association of asthma and its genetic predisposition with the risk of severe COVID-19 [published online ahead of print 2020]. J Allergy Clin Immunol. https://doi.org/10.1016/j.jaci.2020.06.001.

      An Australian pediatric study retrospectively included all pediatric patients (aged 0-18 years) who presented to the emergency department of the newly established Respiratory Infection Clinic who tested for SARS-CoV-2 from the day of the first positive confirmed case. One in 4 COVID-19–positive patients had a comorbidity, which was asthma (1 of 4 [25%]).
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      In the group of SARS-negative subjects, asthma was the most common comorbidity, with a prevalence of 11%.
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      The “usual” prevalence of asthma among young Australians aged 0 to 17 years was 10.3% in the period 2017 to 2018.
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      Overall, in most countries around the world, patients with asthma were not reported with higher rates of COVID-19 infection compared with the general population in the corresponding area. There is a big difference in the incidence of COVID-19 in patients with asthma among different areas and countries, with some of them reporting low rates of COVID-19 with asthma, probably due to the multiple factors including the rigorous self-protection awareness and low proportion of non–type 2 phenotypes.

       Severity of COVID-19 in patients with asthma

      Except for the susceptibility of patients with asthma to COVID-19, another important issue is whether there is a shift in severity and mortality among COVID-19 patients with asthma compared with those without. Among the 548 patients with COVID-19 admitted to Tongji Hospital, there were 5 with asthma, including 2 of 279 with nonsevere asthma (0.7%) and 3 of 269 with severe asthma (1.1%). There was no significant difference in asthma prevalence between patients with severe and nonsevere COVID-19.
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      Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan.
      Saudi Arabia reported that the prevalence of asthma was 3 (2.9%), 0 (0%), and 1 (7.7%) in patients with mild, moderate, and severe COVID-19, respectively.

      Shabrawishi M, Al-Gethamy MM, Naser AY, Ghazawi MA, Alsharif GF, Obaid EF, et al. Clinical, radiological and therapeutic characteristics of patients with COVID-19 in Saudi Arabia [published online ahead of print 2020]. Medrxiv. https://doi.org/10.1101/2020.05.07.20094169. Available at: http://medrxiv.org/cgi/content/short/2020.05.07.20094169.

      In the Brazilian retrospective study including 51,770 COVID-19 cases, the prevalence of “moderate to severe asthma” is 1.5%.
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      Adults at high-risk of severe coronavirus disease-2019 (Covid-19) in Brazil.
      Asthma was identified in 5.2% of patients with COVID-19 in a Spanish study, with a lower prevalence rate of 3.7% in fatal cases and 5.5% in live discharge case.
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      A cohort of patients with COVID-19 in a major teaching hospital in Europe.
      An Italian study of 355 lethal patients’ cases with COVID-19 reported that comorbidities were associated with an increased mortality risk, but asthma was not mentioned on the list of comorbidities.
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      Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy.
      A study conducted in Switzerland included 200 patients with COVID-19 hospitalized in the Lausanne University Hospital and reported 4.0% asthma prevalence, 1 of 37 (2.7%) with asthma among those patients who required mechanical ventilation and 7 of 163 (4.3%) with asthma among those patients who did not require mechanical ventilation.

      Regina J, Papadimitriou-Olivgeris M, Burger R, Filippidis P, Tschopp J, Desgranges F, et al. Epidemiology, risk factors and clinical course of SARS-CoV-2 infected patients in a Swiss university hospital: an observational retrospective study [published online ahead of print 2020]. medRxiv. https://doi.org/10.1101/2020.05.11.20097741.

      Lieberman-Cribbin et al

      Lieberman-Cribbin W, Rapp J, Alpert N, Tuminello S, Taioli E. The impact of asthma on mortality in patients with COVID-19 [published online ahead of print 2020]. Chest. https://doi.org/10.1016/j.chest.2020.05.575.

      describe results from the Mount Sinai Health System and found that there was no statistically significant association between asthma status and mortality among patients with COVID-19. Therefore, we provisionally conclude that asthma is not associated with a higher risk of mortality among patients with COVID-19 who have a history of asthma. So far, there is no clear evidence that patients with asthma are more likely to be infected with SARS-CoV-2 or to become severely ill.

       The phenotype of asthma patients with COVID-19

      Although there is yet little information about asthma phenotypes in patients with COVID-19, we may speculate that patients with asthma with different phenotype hold various susceptibility and severity of COVID-19. The study by the UK Biobank reported that adults with asthma had a higher risk of severe COVID-19, which was driven by the increased risk in patients with nonallergic asthma.

      Zhu Z, Hasegawa K, Ma B, Fujiogi M, Camargo CA, Liang L. Association of asthma and its genetic predisposition with the risk of severe COVID-19 [published online ahead of print 2020]. J Allergy Clin Immunol. https://doi.org/10.1016/j.jaci.2020.06.001.

      In contrast, the risk of severe COVID-19 was not significantly elevated in patients with allergic asthma.

       Potential lower risk of patients with type 2 asthma to develop COVID-19

      Type 2 asthma is characterized by TH2-driven airway inflammation with increased levels of IL-4, IL-5, and IL-13 production, blood and airway eosinophilia, and (in the case of allergic asthma) increased levels of total and allergen-specific IgE antibodies associated with mast cell activation. Lymphopenia, particularly due to the reduction of T cells, is a well-established marker for COVID-19 severity, and because patients with asthma with COVID-19 have increased numbers and activation-level T cells and show a less severe course of the disease, it is suggested that both CD4+ and CD8+ T cells reduce the destructive power of SARS-CoV-2.

      Shi W, Gao Z, Ding Y, Zhu T, Zhang W, Xu Y. Clinical characteristics of COVID-19 patients combined with allergy [published online ahead of print 2020]. Allergy. https://doi.org/10.1111/ALL.14434.

      Angiotensin-converting enzyme-2 (ACE-2) serves as a major receptor for SARS-CoV-2 to enter host cells via its structural spike glycoprotein (Fig 2). ACE-2 is predominantly expressed on nasal epithelium, lung, heart, kidney, and intestine, but it is rarely expressed on immune cells.
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      ,
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      Markedly reduced levels of ACE-2 transcripts have been detected in nasal and bronchial epithelial cells of allergy sufferers, and this is associated with allergen exposure, allergen sensitization, and high IgE levels,
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      Figure thumbnail gr2
      Fig 2The impact of asthma endotypes on infection of airway epithelium with SARS-CoV-2, development and progression of COVID-19. The 2 major asthma endotypes, type 2 asthma and non–type 2 asthma, are defined by unique inflammatory patterns on the level of adaptive immunity and effector cell responses. Type 2 asthma is characterized by the presence of TH2 cells secreting IL-4, IL-5, and IL-13. These cytokines have a strong impact on the regulation of helper-cell subsets, airway epithelial function, and regulation of effector cell responses, including eosinophils and mast cells. In contrast, non–type 2 asthma is defined by the presence of TH1 cells and/or TH17 cells among other effector T-cell responses. The subset of these patients shows vascular and metabolic comorbidities, which are underlined by the presence of subclinical chronic inflammatory responses (eg, activation of IL-1 signaling pathways). EDN, Eosinophil-derived neurotoxin; pDC, plasmacytoid dendritic cell; T2D, type 2 diabetes.
      However, there is an increasing amount of data providing evidence that ICSs are associated with reduction in ACE-2 and transmembrane proteases serine 2 (TMPRSS2) gene expression.
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      This presumably occurs by a mechanism independent of any ICS-mediated suppression of TH2 inflammation. In addition, there is evidence to support that taking ICSs may be beneficial in dealing with coronavirus infections, based on in vitro studies with coronavirus application and cytokine production as an outcome.
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      Host TMPRSS2 cleaves a viral spike protein and facilitates virus fusion to the cellular membrane.
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      In contrast to ACE-2, TMPRSS2 gene expression is upregulated under TH2 conditions.

      Sajuthi SP, DeFord P, Jackson ND, Montgomery MT, Everman JL, Rios CL, et al. Type 2 and interferon inflammation strongly regulate SARS-CoV-2 related gene expression in the airway epithelium [published online ahead of print 2020]. bioRxiv. 2020 Apr 10;2020.04.09.034454.

      However, there are very few cells coexpressing ACE-2 and TMPRSS2 simultaneously. Therefore, it is questionable whether this increased TMPRSS2 expression favors SARS-CoV-2 infection in patients with allergic asthma.

      Sajuthi SP, DeFord P, Jackson ND, Montgomery MT, Everman JL, Rios CL, et al. Type 2 and interferon inflammation strongly regulate SARS-CoV-2 related gene expression in the airway epithelium [published online ahead of print 2020]. bioRxiv. 2020 Apr 10;2020.04.09.034454.

      Blood eosinophilia is an established biomarker for type 2 inflammation,
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      T-helper type 2-driven inflammation defines major subphenotypes of asthma.
      and eosinophils have important antiviral properties. This includes single-stranded RNA activating eosinophils via Toll-like receptor-7/myeloid differentiation primary response 88-dependent mechanisms,
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      Eosinophils contribute to innate antiviral immunity and promote clearance of respiratory syncytial virus.
      and eosinophil-derived neurotoxin, which serves as a ribonuclease.
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      Recombinant human eosinophil-derived neurotoxin/RNase 2 functions as an effective antiviral agent against respiratory syncytial virus.
      Conversely, eosinopenia has been observed in patients with severe COVID-19, and blood cell counts normalize following lopinavir treatment, suggesting that they may serve as a marker for improvement.
      • Zhang J.-J.
      • Dong X.
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      • Yan Y.-Q.
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      Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China.
      ,
      • Qin C.
      • Zhou L.
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      Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China.
      ,
      • Liu F.
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      • Zhang Y.
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      • Yan T.
      • Pan K.
      • et al.
      Patients of COVID-19 may benefit from sustained Lopinavir-combined regimen and the increase of eosinophil may predict the outcome of COVID-19 progression.
      In a Russian retrospective study, absolute blood eosinophil counts were below 0.02 × 109/L in 85.7% of patients with asthma, and no patient showed blood eosinophilia.

      Avdeev S, Moiseev S, Brovko M, Yavorovskiy A, Umbetova K, Akulkina L, et al. Low prevalence of bronchial asthma and chronic obstructive lung disease among intensive care unit patients with COVID-19 [published online ahead of print 2020]. Allergy. https://doi.org/10.1111/all.14420.

      Infections with respiratory viruses including rhinovirus, respiratory syncyntial virus, and influenza virus are major triggers for asthma exacerbation, particularly in children.
      • Gibson P.G.
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      • Henry R.L.
      • Pin I.
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      Sputum induction in children.
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      Rhinovirus infections in children: a retrospective and prospective hospital-based study.
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      Respiratory viruses and exacerbations of asthma in adults.
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      Community study of role of viral infections in exacerbations of asthma in 9-11 year old children.
      Moreover, asthma has consistently been 1 of the most frequent comorbidities among patients hospitalized because of influenza. In contrast, this is not always the case for SARS-CoV-2. We hypothesize that the main reason for this is a high prevalence of type 2 airway signatures, even in nonatopic children.

      Sajuthi SP, DeFord P, Jackson ND, Montgomery MT, Everman JL, Rios CL, et al. Type 2 and interferon inflammation strongly regulate SARS-CoV-2 related gene expression in the airway epithelium [published online ahead of print 2020]. bioRxiv. 2020 Apr 10;2020.04.09.034454.

      This could be a major reason why the prevalence of COVID-19 is relatively low in this age group, particularly because allergic, eosinophilic asthma is the major asthma endotype among young patients with asthma. Mast cells also contribute to combat viral infections and, in particular, SARS-CoV-2, because they are a major source of IFN.
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      Mast cell responses to viruses and pathogen products.
      ,
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       Potential role of allergen-induced cross-reactive T-cell responses to SARS-CoV-2 among patients with asthma

      T-cell responses against SARS-CoV-2 are first detectable approximately 1 week following symptom onset and remain in convalescence, while numbers of virus-specific T cells correlate with neutralization antibody titers.
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      Detection of SARS-CoV-2-specific humoral and cellular immunity in COVID-19 convalescent individuals.
      Patients who recovered from SARS-CoV infection developed long-lived virus-specific T memory cells, detectable up to 2 years following infection resolution.
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      ,
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      • et al.
      Long-lived effector/central memory T-cell responses to severe acute respiratory syndrome coronavirus (SARS-CoV) S antigen in recovered SARS patients.
      Heterologous immunity (HI) has been originally described as a consequence of previous infections, which alter the immune response to a subsequent infection with a different pathogen.
      • Welsh R.M.
      • Selin L.K.
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      This mechanism may occur between closely related or completely unrelated antigens. HI may ultimately alter the outcome of infections due to cross-reactive recognition and immune protection or due to induction of immunopathology.
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      Protective heterologous antiviral immunity and enhanced immunopathogenesis mediated by memory T cell populations.
      Cellular-mediated HI may be elicited by means of T-cell receptor cross-reactivity, recognizing similar but distinct antigens or by cytokine-induced nonspecific activation of T cells.
      • Welsh R.M.
      • Che J.W.
      • Brehm M.A.
      • Selin L.K.
      Heterologous immunity between viruses.
      We have previously reported on influenza-induced heterologous immune responses against allergens, which mediated protection from experimental allergic asthma.
      • Skevaki C.
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      Influenza-derived peptides cross-react with allergens and provide asthma protection.
      We recently hypothesized that SARS-CoV-2 may show protein sequence homology to allergens, which may generate cross-reactive T-cell epitopes. We thus applied 2 independent but complementary bioinformatic approaches to identify potentially cross-reactive allergen T-cell and SARS-CoV-2 T-cell epitopes. Our in silico analysis revealed numerous candidate epitope pairs, including previously published as well as predicted peptides, and highlighted an important role of MHC class I aeroallergens in this regard
      • Balz K.
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      • Cemic F.
      • Heger V.
      • Renz H.
      • et al.
      Homologies between SARS-CoV-2 and allergen proteins may direct T cell-mediated heterologous immune responses.
      (Fig 2). In hosts, who are sensitized to 1 of the predicted allergens, the identified similarities with the SARS-CoV-2 proteome may be protective or harmful. Allergen-specific T cells may develop a memory-type response against heterologous SARS-CoV-2 epitopes, which is by definition faster and more efficient. Quite recently, the role of SARS-CoV-2–specific T cells in exposed and nonexposed individuals has been discussed, which further underlines the potential importance of HI in COVID-19 outcome.
      • Grifoni A.
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      ,

      Braun J, Loyal L, Frentsch M, Wendisch D, Georg P, Kurth F, et al. Presence of SARS-CoV-2 reactive T cells in COVID-19 patients and healthy donors [published online ahead of print 2020]. Nature. https://doi.org/10.1038/s41586-020-2598-9.

      Specifically, it was suggested that cross-reactive CD4+ T cells in some populations may be recruited into an amplified primary SARS-CoV-2–specific response. Therefore, patients with allergic asthma may carry potential SARS-CoV-2 cross-reactive T cells in their T-cell repertoire if they are sensitized to the respective cross-reactive allergens. This would provide a significant advantage for patients with allergic asthma over other patients with asthma in combating SARS-CoV-2 infections. Further experimental studies are underway to provide supporting functional data and confirm this concept.

       Progression of COVID-19 in patients with type 2 asthma

      We hypothesize that if SARS-CoV-2 succeeds to establish clinical manifestations in patients with allergic asthma, the risk for disease progression is higher as compared with that in patients with nonallergic asthma with COVID-19. This may occur because of several reasons: (1) TH2 inflammation counteracts TH1 immunity and limits the production of proinflammatory cytokines (eg, IL-1β, TNF-α, IL-6, and IL-12), which are required to combat viral infections; (2) an impaired production of type I and type III IFNs (IFN-α, IFN-β, IFN-λ) by airway epithelial cells has been described in patients with asthma in response to viral infections
      • Cakebread J.A.
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      Exogenous IFN-β has antiviral and anti-inflammatory properties in primary bronchial epithelial cells from asthmatic subjects exposed to rhinovirus.
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      Bronchial mucosal IFN-α/β and pattern recognition receptor expression in patients with experimental rhinovirus-induced asthma exacerbations.
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      Counterregulation between the FcepsilonRI pathway and antiviral responses in human plasmacytoid dendritic cells.
      ; and (3) plasmocytoid dendritic cells represent the primary source of IFN-α to defend against viral infections and IgE negatively regulates IFN-α production through inhibition of TLR signaling in these cells.

      Carli G, Cecchi L, Stebbing J, Parronchi P, Farsi A. Is asthma protective against COVID-19? [published online ahead of print 2020]. Allergy. https://doi.org/10.1111/ALL.14426.

      • Gonzales-van Horn S.R.
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       COVID-19 in patients with non–type 2 asthma

      There is circumstantial evidence that patients suffering from non–type 2 asthma are at a higher risk for progression to severe COVID-19. Non–type 2 is defined as patients with asthma with other inflammatory profile such as TH1- or TH17-dominated inflammation including patients with chronic obstructive pulmonary disease and asthma. A recently published nationwide South Korean study reported that among patients with asthma, particularly nonallergic asthma, there is a greater risk of susceptibility to SARS-CoV-2 infection and severe clinical outcomes of COVID-19.

      Yang JM, Koh HY, Moon SY, Yoo IK, Ha EK, You S, et al. Allergic disorders and susceptibility to and severity of COVID-19: a nationwide cohort study [published online ahead of print 2020]. J Allergy Clin Immunol. https://doi.org/10.1016/j.jaci.2020.08.008.

      Elderly patients with asthma are at a higher risk for morbidity and mortality than younger patients with asthma. In many of these individuals, the inflammatory response is non–type 2-mediated,
      • Dunn R.M.
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      • Wechsler M.E.
      Asthma in the elderly and late-onset adult asthma.
      and the inflammatory endotype is dominated by type 1 and/or type 17 T-cell responses. A molecular phenotype is characterized by inflammasome-associated and metabolic/mitrochrondrial pathways.
      • Kuo C.-H.S.
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      • Rowe A.
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      T-helper cell type 2 (Th2) and non-Th2 molecular phenotypes of asthma using sputum transcriptomics in U-BIOPRED.
      Many of these patients with asthma suffer from comorbidities including obesity, type 2 diabetes, and hypertension as part of the metabolic syndrome.
      • Huang C.
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      This endotype is particularly prevalent in inner-city adults
      • Fitzpatrick S.
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      Obesity is associated with increased asthma severity and exacerbations, and increased serum immunoglobulin E in inner-city adults.
      and among African Americans.
      • White S.R.
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      Evidence for an IL-6-high asthma phenotype in asthmatic patients of African ancestry.
      CD147 activation suppresses several T-cell functions through the inhibition of nuclear factor of activated T-cell pathways.
      • Yao H.
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      Important functional roles of basigin in thymocyte development and T cell activation.
      ,
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      CD147 inhibits the nuclear factor of activated T-cells by impairing Vav1 and Rac1 downstream signaling.
      CD147 expression correlates positively with body mass index in patients with COVID-19, and is also upregulated by high glycose concentrations.
      • Bao W.
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      Monocyte CD147 is induced by advanced glycation end products and high glucose concentration: possible role in diabetic complications.
      IL-6 serves as a biomarker for systemic inflammation and metabolic dysfunction as well as for severity in these patients with asthma.
      • Peters M.C.
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      Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts.
      This subset of patients with asthma may be particularly susceptible to develop severe COVID-19. It is striking that increased cytokine levels with particularly high levels of IL-6 are characteristic for patients with severe COVID-19 as well.
      • Pedersen S.F.
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      It is well established that patients with COVID-19 with these comorbidities are at a higher risk for severity and mortality (L. Qin, C. Zhang, J. Yue, X. Min, unpublished data, 2020). The increased expression of ACE-2 detected in subgroups
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      with type 2 diabetes, chronic obstructive pulmonary disease, African Americans, smokers, and males
      • Peters M.C.
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      • DeFord P.
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      further contributes to this.
      • Peters M.C.
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      • DeFord P.
      • Christenson S.
      • Rios C.L.
      • Montgomery M.T.
      • et al.
      COVID-19 related genes in sputum cells in asthma: relationship to demographic features and corticosteroids.
      ,
      • Leung J.M.
      • Yang C.X.
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      • Hackett T.-L.
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      ACE-2 expression in the small airway epithelia of smokers and COPD patients: implications for COVID-19.
      This may be regulated through IL-17 and supported because of the positive correlation between ACE-2 expression and TH17 gene signatures.
      • Bradding P.
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      • Howarth P.H.
      • Choy D.F.
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      The latter are more frequent among females and based on known age- and sex-induced influences on immune responses, it is likely that such skewing could also take place independently of the presence of asthma.
      In contrast to patients with allergic asthma, patients with asthma with this endotype have a low number of blood eosinophils
      • Bradding P.
      • Richardson M.
      • Hinks T.S.C.
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      • Choy D.F.
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      and therefore lack the contribution of these effector cells in anti–SARS-COV-2 defense. CD147, also termed basigin, acts as a receptor for SARS-CoV-2 in T cells and epithelial cells, and humanized anti-CD147 antibody treatment has been shown to reduce inflammation and to improve patients with severe COVID-19.
      • Wang K.
      • Chen W.
      • Zhou Y.-S.
      • Lian J.-Q.
      • Zhang Z.
      • Du P.
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      SARS-CoV-2 invades host cells via a novel route: CD147-spike protein.

      Wang X, Xu W, Hu G, Xia S, Sun Z, Liu Z, et al. SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion [published online ahead of print 2020]. Cell Mol Immunol. https://doi.org/10.1038/s41423-020-0424-9.

      Bian H, Zheng Z-H, Wei D, Zhang Z, Kang W-Z, Hao C-Q, et al. Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial [published online ahead of print 2020]. medRxiv. https://doi.org/10.1101/2020.03.21.20040691.

       Conclusions

      This model may provide a comprehensive explanation for regional differences in asthma prevalence among patients with COVID-19 in North America, Europe, Russia, China, and other nations around the world.
      However, to further validate this novel concept, more data and studies are required. Many of the so far published studies are retrospective and are nondiscriminating regarding asthma phenotypes. There is a considerable lack of additional clinical and immunologic parameters. Deep endotyping of patients with COVID-19 and asthma would be required to get a better understanding about the immunologic and metabolic association between these 2 entities. Also, on the level of virus-host interactions with regard to the cellular entry mechanism used by the virus, more data on the transcriptional and translational level of receptor regulation is certainly needed. In addition, there is a lack of longitudinal prospective studies.
      A high proportion of patients with type 2 (allergic, eosinophilic) asthma in the population may help to limit SARS-CoV-2 dissemination. However, if patients with allergic asthma develop COVID-19, they may have a higher risk of disease progression. This is mainly due to diminished intrinsic IFN signaling pathways. This might be in contrast to regions with a relatively high population of patients with non–type 2 asthma, which are in particular elderly patients with metabolic comorbidities such as obesity, metabolic syndrome, and glucose dysregulation. This group of patients with asthma has a different inflammatory profile, and due to the chronic subclinical inflammation associated with the metabolic dysregulation, there is circumstantial evidence that the immune system is already (pre-) programmed to develop hyperinflammation in the context of a cytokine storm in association with COVID-19. In both situations, patients with asthma with metabolic dysregulation and patients with COVID-19 with associated hyperinflammation, the IL-6 signaling pathways contribute to the disease among other proinflammatory cytokines.
      This concept may illustrate that different asthma endotypes have a differential impact on the infection of airway epithelial cells with SARS-CoV-2, and the development and the progression of COVID-19. This concept requires further clinical and experimental evidence, and we propose to include immunologic endotyping in SARS-CoV-2–infected patients with regard to the presence (or absence) of underlying inflammatory profiles on the level of both innate and adaptive immunity. This could have further implications for immunomodulatory therapies in patients with COVID-19 with asthma comorbidity.
      New data are emerging rapidly and deepening our understanding about COVID-19 in patients with asthma/allergy. From the present perspective, current recommendations for treatment of asthma in the context of COVID-19 should not be changed. Patients should receive guideline-based pharmacological treatment including ICSs and biological therapies if needed.

      Supplementary data

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