Protective mechanisms of allergic asthma in COVID-19.

The identification of protective and risk factors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been critical to addressing the coronavirus disease 2019 (COVID-19) pandemic. Although multiple risk factors are established, less is known about specific protective factors. The association of allergy and asthma with COVID-19 has been of particular interest, as these are common conditions that often predispose to respiratory illnesses, but in the case of SARS-CoV-2, asthma may paradoxically play a protective role. In this review, we discuss epidemiologic associations between asthma and COVID-19 disease severity, the potential role of asthma therapies, and the mechanisms by which type 2 (T2) inflammation may lead to reduced susceptibility to SARS-CoV-2 infection. Early in the pandemic, it was hypothesized that asthma and respiratory allergy would be significant risk factors for severe COVID-19. The rationale for this hypothesis was multifold. Asthma is a chronic respiratory disease, and patients with allergic asthma are vulnerable to other respiratory viral infections. Early epidemiologic studies reported conflicting findings on the association of asthma with adverse outcomes of COVID-19. For instance, Williamson et al1Williamson E.J. Walker A.J. Bhaskaran K. Bacon S. Bates C. Morton C.E. et al.Factors associated with COVID-19-related death using OpenSAFELY.Nature. 2020; 584: 430-436Crossref PubMed Scopus (3585) Google Scholar showed severe asthma in adults as a risk factor for COVID-19 mortality but did not stratify the data by the type of asthma. Zhu et al2Zhu Z. Hasegawa K. Ma B. Fujiogi M. Camargo Jr., C.A. Liang L. Association of asthma and its genetic predisposition with the risk of severe COVID-19.J Allergy Clin Immunol. 2020; 146: 327-329.e4Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar later showed data stratified by type of asthma, also in adults, and found specifically that allergic asthma (defined as asthma with eczema, food allergy, and/or allergy rhinitis) was not a significant risk factor. Later, the prospective HEROS study3Seibold M.A. Moore C.M. Everman J.L. Williams B.J.M. Nolin J.D. Fairbanks-Mahnke A. et al.Risk factors for SARS-CoV-2 infection and transmission in households with children with asthma and allergy: a prospective surveillance study.J Allergy Clin Immunol. 2022; 150: 302-311Abstract Full Text Full Text PDF PubMed Google Scholar confirmed that asthma in children did not increase the risk of SARS-CoV-2 infection and that food allergy was in fact associated with lower infection risk. Thus, as data have emerged, it has become evident that COVID-19 risk and mortality are not increased in individuals with asthma; rather, allergic asthma may confer an unexpected level of protection. The data from large cohorts investigating corticosteroid use for asthma or other therapies (including biologics) and COVID-19 severity are inconclusive. A large study in the United Kingdom that included 818,490 adults with asthma demonstrated that individuals with asthma who were prescribed a high-dose inhaled corticosteroid (ICS) were at increased risk of COVID-19–related death, whereas those given a low or medium dose were not. Importantly, however, the authors’ sensitivity analysis of these data suggested that the harmful association was due to other health differences found in individuals prescribed ICS rather than the treatment itself.4Schultze A. Walker A.J. MacKenna B. Morton C.E. Bhaskaran K. Brown J.P. et al.Risk of COVID-19-related death among patients with chronic obstructive pulmonary disease or asthma prescribed inhaled corticosteroids: an observational cohort study using the OpenSAFELY platform.Lancet Respir Med. 2020; 8: 1106-1120Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar Another retrospective study of 71,182 adults with asthma reported that use of ICS in asthma reduced risk for hospitalization due to COVID-19.5Izquierdo J.L. Almonacid C. González Y. Del Rio-Bermudez C. Ancochea J. Cárdenas R. et al.The impact of COVID-19 on patients with asthma.Eur Respir J. 2021; 57Crossref PubMed Scopus (131) Google Scholar In a study of 80,602 adults with asthma from Israel,6Adir Y. Humbert M. Saliba W. COVID-19 risk and outcomes in adult asthmatic patients treated with biologics or systemic corticosteroids: nationwide real-world evidence.J Allergy Clin Immunol. 2021; 148: 361-367.e13Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar use of either oral corticosteroids (OCSs) or asthma biologics was not associated with greater risk of SARS-CoV-2 infection; however, chronic or repeated use of an OCS was associated with an increase for moderate or severe COVID-19 disease and all-cause mortality. Similarly, a surveillance study of children aged 5 to 17 years in Scotland found that children with asthma who had 2 or more courses of an OCS or hospital admission for severe asthma in the previous 2 years were at greater risk of hospital admission and severe COVID-19 disease.7Shi T. Pan J. Katikireddi S.V. McCowan C. Kerr S. Agrawal U. et al.Risk of COVID-19 hospital admission among children aged 5-17 years with asthma in Scotland: a national incident cohort study.Lancet Respir Med. 2022; 10: 191-198Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar In summary, asthma therapies do not increase the risk of severe COVID-19; rather, unstable asthma and associated comorbidities may increase the risk of severe COVID-19. Several hypotheses and possible mechanisms by which asthma and/or T2 inflammation may protect against SARS-CoV-2 have been proposed; they include altered expression of viral entry proteins, altered airway epithelial biology, mucus hypersecretion preventing viral penetration, effects of corticosteroids or biologics, and others. A few of these mechanisms have now been studied and offer compelling evidence as to the likely protective effects of T2 inflammation against SARS-CoV-2. SARS-CoV-2 infects humans by binding angiotensin-converting enzyme 2 (ACE2) on the surface of epithelial cells, and it is facilitated by cofactors including transmembrane protease, serine 2 (TMPRSS2), transmembrane protease, serine 4 (TMPRSS4), and furin. On the basis of the notion of ACE2 expression as a proxy for SARS-CoV-2 infection risk, several groups8Jackson D.J. Busse W.W. Bacharier L.B. Kattan M. O’Connor G.T. Wood R.A. et al.Association of respiratory allergy, asthma, and expression of the SARS-CoV-2 receptor ACE2.J Allergy Clin Immunol. 2020; 146: 203-206.e3Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar postulated that the level of airway ACE2 expression might influence disease susceptibility, and they identified consistently lower expression in individuals with allergies and asthma than in matched individuals without allergy. Stimulation with the T2 cytokine IL-13 further reduces ACE2 expression in airway epithelium.8Jackson D.J. Busse W.W. Bacharier L.B. Kattan M. O’Connor G.T. Wood R.A. et al.Association of respiratory allergy, asthma, and expression of the SARS-CoV-2 receptor ACE2.J Allergy Clin Immunol. 2020; 146: 203-206.e3Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar Moreover, ACE2 expression showed a negative association with T2 inflammation networks. Despite this intriguing observation, no study to date has conclusively found that the lower ACE2 expression due to T2 inflammation is a mechanism of protection against SARS-CoV-2 infection. Bonser et al9Bonser L.R. Eckalbar W.L. Rodriguez L. Shen J. Koh K.D. Ghias K. et al.The type 2 asthma mediator IL-13 inhibits severe acute respiratory syndrome coronavirus 2 infection of bronchial epithelium.Am J Respir Cell Mol Biol. 2022; 66: 391-401Crossref PubMed Scopus (20) Google Scholar directly explored the protective mechanisms of T2 inflammation by using IL-13 stimulation of bronchial epithelial cells cultured at the air-liquid interface (ALI). They identified a dramatic decrease in viral replication to below the limit of detection that was due to IL-13 stimulation. This decrease was found to be due in part to the increased mucus barrier, which could inhibit SARS-CoV-2 infection; however, IL-13 stimulation reduced viral RNA whether mucus was present or absent. Furthermore, CRISPR-Cas9 targeting of SPDEF, a key regulator of MUC5AC and mucus-producing goblet cells, did not abolish the antiviral effects of IL-13. Therefore, even in the absence of the mucus barrier, IL-13 inhibited SARS-CoV-2 infection through other unidentified mechanisms. Morrison et al10Morrison C.B. Edwards C.E. Shaffer K.M. Araba K.C. Wykoff J.A. Williams D.R. et al.SARS-CoV-2 infection of airway cells causes intense viral and cell shedding, two spreading mechanisms affected by IL-13.Proc Natl Acad Sci U S A. 2022; 119e2119680119Crossref Scopus (26) Google Scholar studied the viral and cell-shedding mechanisms in SARS-CoV-2–infected airway epithelial cells cultured at the ALI and the role of IL-13 stimulation in regulating these processes. They demonstrated elevated tropism of SARS-CoV-2 in ciliated cells versus in goblet cells and used electron microscopy to show that large clusters of SARS-CoV-2 virions formed in the ciliated cells, causing epithelial damage and viral shedding. In contrast, goblet cells did not form virion-filled vacuoles. They further demonstrated that IL-13 stimulation prevented epithelial damage and cell shedding versus in cultures with no IL-13 stimulation. Although IL-13 stimulation increased MUC5AC expression, removal of mucus and knockout of MUC5AC still resulted in decreased SARS-CoV-2–infected cells with IL-13 stimulation. Therefore, this result demonstrated protective effects of IL-13 irrespective of mucus hypersecretion, which is consistent with the findings of Bonser et al.9Bonser L.R. Eckalbar W.L. Rodriguez L. Shen J. Koh K.D. Ghias K. et al.The type 2 asthma mediator IL-13 inhibits severe acute respiratory syndrome coronavirus 2 infection of bronchial epithelium.Am J Respir Cell Mol Biol. 2022; 66: 391-401Crossref PubMed Scopus (20) Google Scholar In a recent study, we11Doni Jayavelu N. Altman M.C. Benson B. Dufort M. Vanderwall E.R. Rich L.M. et al.Type-2 inflammation reduces SARS-CoV-2 replication in the airway epithelium in allergic asthma through functional alteration of ciliated epithelial cells.J Allergy Clin Immunol. 2023; 152: 56-67Abstract Full Text Full Text PDF Scopus (0) Google Scholar identified key genes and specific epithelial cell populations involved in T2 protective mechanisms against SARS-CoV-2 infection in allergic asthma (Fig 1). Bulk RNA sequencing of ALI cultures infected with SARS-CoV-2 demonstrated that IL-13 stimulation significantly reduced SARS-CoV-2 replication in epithelium from individuals with allergic asthma, which was similar to the results obtained by Bosner et al9Bonser L.R. Eckalbar W.L. Rodriguez L. Shen J. Koh K.D. Ghias K. et al.The type 2 asthma mediator IL-13 inhibits severe acute respiratory syndrome coronavirus 2 infection of bronchial epithelium.Am J Respir Cell Mol Biol. 2022; 66: 391-401Crossref PubMed Scopus (20) Google Scholar and Morrison et al10Morrison C.B. Edwards C.E. Shaffer K.M. Araba K.C. Wykoff J.A. Williams D.R. et al.SARS-CoV-2 infection of airway cells causes intense viral and cell shedding, two spreading mechanisms affected by IL-13.Proc Natl Acad Sci U S A. 2022; 119e2119680119Crossref Scopus (26) Google Scholar; also demonstrated was lower viral replication in epithelium from individuals with allergic asthma than in epithelium from controls without allergy and without asthma. We identified gene sets mediating the reduction in SARS-CoV-2 replication by IL-13 stimulation; these gene sets included pathways with well-established roles in ciliogenesis, including FOXJ1, PIFO, and SNTN. Lower viral transcript levels were closely associated with a downregulation of functional pathways of the ciliated epithelium, as opposed to lower ACE2 expression or increases in goblet cells or mucus secretion pathways. Using single-cell RNA sequencing of ALI cultures, we further detailed specific subsets of relatively undifferentiated and transitional ciliated epithelial cells, common in cultures from donors with allergic asthma and highly responsive to IL-13, that accounted for the impairment of viral replication. Thus, it is likely the decreases in the key ciliary functional proteins in these ciliated cells, including the transcription factor FOXJ1, and corresponding downregulation of axoneme assembly and intraciliary transport machinery could prevent efficient viral replication, resulting in the lower viral levels observed within the ciliated epithelium of individuals with allergic asthma. Contrary to early hypotheses, epidemiologic data have generally concluded that most individuals with allergic asthma are not at higher risk of SARS-CoV-2 infection or COVID-19 mortality than the general population, and in fact, many may be protected against both of these conditions. Additionally, the evidence to date suggests that asthma therapies do not negatively affect COVID-19 severity. Most of this research was conducted early in the pandemic, and it is most directly relevant to the original Alpha and subsequent Delta variants; thus the relevance of these findings for current SARS-CoV-2 variants is less clear, although this remains an area of active research. The consequences of T2 inflammation of the airway epithelium likely mediate this protective clinical effect. Several studies have shown that airway epithelial cells from individuals with allergic asthma do not replicate virus efficiently and IL-13 stimulation can dramatically reduce viral replication and/or shedding. Furthermore, IL-13–driven T2 inflammation alters expression patterns and functions of ciliated epithelial cells in a manner that inhibits viral replication. Increases in goblet cells and mucus secretion due to IL-13 can prevent initial viral infection and shedding. And finally, allergic asthma and IL-13 decrease ACE2 expression in the airway, which may also play a role in preventing the initial viral entry into the airway epithelium in T2 asthma. Likely, it is a combination of these and other effects that results in protection against SARS-CoV-2 due to T2 inflammation. Although these mechanisms have not yet been proved to have direct clinical consequences, they are congruent with the epidemiologic data, and collectively, the literature suggests that T2 inflammation is an unexpected mechanism of protection against SARS-CoV-2.